TW202412784A - Aza-quinazoline compounds and methods of use - Google Patents

Abstract

Substituted aza-quinazoline compounds, conjugates, and pharmaceutical compositions for use in the treatment of cancer are disclosed herein. The disclosed compounds are useful, among other things, in the inhibition of CDK. In certain aspects, the disclosure generally relates to substituted quinolinone amide compounds or salts of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), and (IEE) and pharmaceutical compositions thereof.

Description

Nitrogen-quinazoline compounds and methods of use

Mammalian cell division and proliferation, mediated by the cell cycle, are important and fundamental biological processes that control the production and generation of cells with critical biological functions. The cell cycle is a highly regulated process and responds to a complex set of cellular signals within the cell and externally. A complex network of cell signaling, including both cancer-promoting and cancer-suppressing components, plays a key role in controlling the cell cycle. Gain of function of tumor-promoting components or loss of function of tumor-suppressing products may result in an unregulated cell cycle and subsequent tumor formation.

Cyclin and cyclin-dependent kinases (CDKs) are essential for driving and controlling cell cycle transitions and cell division (34176404). Cyclin is a family of proteins whose expression levels change at different stages of the cell cycle. Cyclin binds and activates CDKs during different stages of the cell cycle, with the process being tightly synchronized, involving the sequential activation of several cyclin-CDK complexes. Of the more than 20 CDKs discovered to date, CDK1, 2, 4, and 6 have been reported to play a direct role in cell cycle progression. The CDK4-cyclin D complex and the CDK6-cyclin D complex are essential for entry into the G1 phase of the cell cycle. The CDK2-cyclin E complex regulates progression from G1 to S phase, while CDK2-cyclin A is required during S phase. The CDK1-cyclin A complex promotes entry into M phase, and mitosis is further regulated by the CDK1-cyclin B complex. Progressive phosphorylation of retinoblastoma (Rb) by CDK4-cyclin D, CDK6-cyclin D, and CDK2-cyclin E releases the GI transcription factor E2F and promotes entry into S phase. Activation of CDK2-cyclin A during early S phase promotes phosphorylation of endogenous substrates, thereby permitting DNA replication and inactivation of E2F, allowing completion of S phase.

Dysregulation of the cell cycle machinery is a hallmark of cancer, leading to overactivation of CDKs and uncontrolled cell division and proliferation. Genetic alterations in genes encoding cyclin D, CDK4/6, and CDK4/6 inhibitory proteins (such as p21, p27) all promote tumor formation. The regulatory cyclin for CDK2, cyclin E, is often overexpressed in cancer. Since tumor development is closely associated with genetic mutations and dysregulation of CDKs and their regulators, CDK inhibitors are suitable for anticancer therapy. CDK inhibitors have been developed as cancer treatments since the early 1990s, with several FDA-approved drugs (palbociclib, ribociclib, and abemaciclib). However, these early generation CDK inhibitors on the market have poor selectivity and high toxicity (such as bone marrow suppression), leading to adverse reactions, thereby limiting the clinical dosage and failing to further benefit patients. There is still an unmet medical need for the development of novel CDK inhibitors with better selectivity and less side effects on normal cells.

The present invention generally relates to substituted quinolinamide compounds or salts of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) and (IEE), and pharmaceutical compositions thereof. The substituted quinolinamide compounds or salts of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) and (IEE) disclosed herein can be used to treat abnormal cell growth, such as cancer, in a subject in need thereof.

In some aspects, a method of treating cancer may comprise administering to a subject in need thereof a compound or pharmaceutically acceptable salt of any one of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) and (IEE).

In certain aspects, the present invention provides a compound represented by formula (I0): wherein A is a ring selected from the following: an optionally substituted carbon ring, an optionally substituted 4- to 8-membered heterocyclic ring, and an optionally substituted isoindoline; ^Z0 is -C(H)- or nitrogen; each of ^Z1 , ^Z2 , and ^Y1 is independently selected from -C( ^R2 ) _2- , -C(O)-, ^-NR3- , -N(C(O) ^R2 )-, -NS( _O2 ) ^R2 , -O-, -S-, -S(O)-, and -S(O) _2- ; each of a and b is independently selected from 1, 2, 3, and 4; each ^R1 is independently selected from halogen, -CN, _-NO2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic ring and optionally substituted heterocyclic ring; m is selected from 0 to 5; each R ² is independently selected from hydrogen, halogen, -CN, -OH, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted -O-cycloalkyl and optionally substituted heterocyclic ring, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R ² and R ³ substituents are combined to form an optionally substituted heterocyclic ring; each R ^R3 is independently selected from hydrogen, an optionally substituted alkyl, _an optionally substituted _C3-4 carbocycle, and an optionally substituted _{3-4 membered heterocycloalkyl; R4 is selected from hydrogen, a halogen, -CN, an optionally substituted C1-4} ^alkyl _{, an} optionally substituted _C3-4 carbocycle, and _an optionally substituted _3-4 membered heterocycloalkyl; each of ^R5 and ^R6 is independently selected from hydrogen, a halogen _{, -CN} , _an optionally substituted _C1-4 alkyl, _an optionally substituted _C3-4 carbocycle, and an optionally substituted _3-4 membered heterocycloalkyl; and ^R7 is selected _from hydrogen and an optionally substituted _C1- wherein if A is an optionally substituted phenyl, m is 1 to 5 and at least one R ¹ is a heterocycloalkyl, wherein if A is an optionally substituted pyridine, an optionally substituted pyrimidine or an optionally substituted pyrimidine, R ₄ is selected from hydrogen, a halogen and -CN, wherein if A is an optionally substituted piperidinesulfonamide, (i) Y ¹ is -C(R ² ) ₂ - and the two R ² substituents are combined to form a ring selected from an optionally substituted heterocycle and an optionally substituted carbocycle, or (ii) R ⁴ is selected from hydrogen, a halogen, a methyl and -CN, and wherein if ^{AR 1 is} and Z ⁰ is CH, then R ⁴ is methyl or cyclopropyl.

In certain aspects, the present invention provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient.

In some aspects, the present invention provides a method for treating cancer, comprising administering to a subject in need thereof a compound or pharmaceutical composition described herein. In some aspects, the present invention provides a method for inhibiting cyclin-dependent kinase (CDK) in a cell using a compound or pharmaceutically acceptable salt or pharmaceutical composition described herein.

Cross-reference to related applications

This application claims the benefit of U.S. Provisional Patent Application No. 63/390,251 filed on July 18, 2022 and U.S. Provisional Patent Application No. 63/512,046 filed on July 5, 2023. The entire contents of the foregoing patent applications are incorporated herein by reference.

Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions will now occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used to practice the present invention. It is intended that the following claims define the scope of the present invention, and that methods and structures within the scope of these claims and their equivalents are covered thereby.

The basic functions of cell regulation, cell division and cell proliferation are controlled by cyclin-dependent kinases (CDKs) activated by regulatory subunits such as cyclins. CDK inhibitors are useful in the treatment of cancer due to the role of CDKs in cell regulation. Increased activity or transient abnormal activation of CDKs has been shown to lead to the development of tumors; tumor development is often associated with changes in CDKs or regulators of CDKs.

CDKs bind to cyclin as a regulatory protein, and in the absence of cyclin, CDKs have minimal kinase activity. The cyclin-CDK complex is an active kinase that is usually regulated by phosphorylation and other binding proteins. There are currently 21 CDKs and 5 CDK-like genes known in the human genome. Although many CDKs have been associated with transcription, CDK2, CDK4, and CDK6 are associated with cell cycle. CDK2 is associated with DNA replication in higher eukaryotes, while CDK4 and CDK6 are associated with various growth regulatory signals.

Overexpression of CDK2 is associated with abnormal regulation of the cell cycle. Cyclin E, a cyclin partner of CDK2, binds to CDK2 to form an active kinase complex. The CDK2-cyclin E complex is critical in the regulation of the G1/S transition, centrosome duplication, and histone biosynthesis. Processive phosphorylation releases the G1 transcription factor E2F and promotes entry into the S phase. Another cyclin partner of CDK2, cyclin A, binds and activates CDK2 during the initial stages of the S phase and promotes phosphorylation of endogenous substrates, which allows DNA replication and inactivation of E2F, allowing the S phase to be completed.

CDK4 and CDK6 are also involved in the cell cycle. CDK4 and CDK6 inhibitors can arrest the cell cycle from G1 to S phase by blocking the phosphorylation of Rb protein and inhibiting the proliferation of Rb-positive tumor cells. In addition to cell cycle activity, CDK4 and CDK6 inhibitors can also inhibit tumor growth through other mechanisms, including (but not limited to) inducing senescence, promoting anti-tumor immune responses, regulating cell metabolism, and enhancing cell growth inhibition caused by signaling pathway inhibitors. Definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

Unless otherwise specified, as used in this specification and the accompanying claims, the following terms have the meanings specified below.

"Amine" refers to a _-NH2 group.

"Cyano" refers to a -CN group.

"Nitro" refers to the _-NO2 radical.

"Oxygen" refers to the -O- group.

"Oxy" refers to a =O group.

"Thione" refers to a =S group.

"Imine" refers to a =N-H group.

"Oxime" refers to a =N-OH group.

"Hydrazino" refers to a =N- _NH2 radical.

"Alkyl" refers to a straight or branched chain hydrocarbon radical consisting only of carbon and hydrogen atoms, containing no unsaturation, and having from one to fifteen carbon atoms (e.g., _C1 - _C15 alkyl). In certain embodiments, the alkyl group contains from one to thirteen carbon atoms (e.g., _C1 - _C13 alkyl). In certain embodiments, the alkyl group contains from one to eight carbon atoms (e.g., _C1 - _C8 alkyl). In other embodiments, the alkyl group contains from one to five carbon atoms (e.g., _C1 - _C5 alkyl). In other embodiments, the alkyl group contains from one to four carbon atoms (e.g., _C1 - _C4 alkyl). In other embodiments, the alkyl group contains from one to three carbon atoms (e.g., _C1 - _C3 alkyl). In other embodiments, the alkyl group contains from one to two carbon atoms (e.g., _C1 - _C2 alkyl). In other embodiments, the alkyl group contains one carbon atom (e.g., _C1 alkyl). In other embodiments, the alkyl group contains five to fifteen carbon atoms (e.g., C ₅ -C ₁₅ alkyl). In other embodiments, the alkyl group contains five to eight carbon atoms (e.g., C ₅ -C ₈ alkyl). In other embodiments, the alkyl group contains two to five carbon atoms (e.g., C ₂ -C ₅ alkyl). In other embodiments, the alkyl group contains three to five carbon atoms (e.g., C ₃ -C ₅ alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (dibutyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tertiary butyl), 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond.

"Heteroalkyl" refers to an alkyl group as defined above having one or more carbon atoms replaced by a heteroatom, such as wherein the heteroatom is individually selected from N, O and S at each replacement position. Additional heteroatoms may also be suitable, including, but not limited to, B, Al, Si and P. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O) ₂ -. For example, heteroalkyl groups may include ethers, thioethers and alkylamines. A heteroalkyl group consists of the specified number of carbon atoms and may include one or more heteroatoms selected from the group consisting of O, N, Si and S, wherein the nitrogen heteroatom may be quaternary ammonium as appropriate. The heteroatoms O, N and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position where the _alkyl group is attached to the rest of the molecule. Two heteroatoms may be consecutive, such as, for example, _-CH2NHOCH3 and _-CH2OSi ( _CH3 ) ₃ . The heteroalkyl group may include any specified number of carbon atoms as defined herein and in the definition of alkyl.

"Alkoxy" refers to a radical of the formula -O-alkyl bonded through an oxygen atom, wherein alkyl is an alkyl chain as defined above.

"Alkenyl" refers to a straight or branched alkyl chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, alkenyl contains from two to eight carbon atoms. In other embodiments, alkenyl contains from two to four carbon atoms. Alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like.

"Alkynyl" refers to a straight or branched alkyl chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon reference bond, having from two to twelve carbon atoms. In certain embodiments, the alkynyl group contains from two to eight carbon atoms. In other embodiments, the alkynyl group contains from two to six carbon atoms. In other embodiments, the alkynyl group contains from two to four carbon atoms. The alkynyl group is attached to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

"Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical, consists only of carbon and hydrogen, contains no unsaturation, and has from one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is connected to the rest of the molecule and to the radical through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical are one carbon in the alkylene chain or any two carbons within the chain. In certain embodiments, the alkylene contains from one to eight carbon atoms (e.g., _C1 - _C8 alkylene). In other embodiments, the alkylene contains from one to five carbon atoms (e.g., _C1 - _C5 alkylene). In other embodiments, the alkylene group contains one to four carbon atoms (e.g., C ₁ -C ₄ alkylene). In other embodiments, the alkylene group contains one to three carbon atoms (e.g., C ₁ -C ₃ alkylene). In other embodiments, the alkylene group contains one to two carbon atoms (e.g., C ₁ -C ₂ alkylene). In other embodiments, the alkylene group contains one carbon atom (e.g., C ₁ alkylene). In other embodiments, the alkylene group contains five to eight carbon atoms (e.g., C ₅ -C ₈ alkylene). In other embodiments, the alkylene group contains two to five carbon atoms (e.g., C ₂ -C ₅ alkylene). In other embodiments, the alkylene group contains three to five carbon atoms (e.g., C ₃ -C ₅ alkylene).

"Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical, consists solely of carbon and hydrogen, contains at least one carbon-carbon double bond, and has two to twelve carbon atoms. The alkenylene chain is connected to the rest of the molecule via a single bond and to the radical via a single bond. In certain embodiments, the alkenylene group comprises two to eight carbon atoms (e.g., _C2 - _C8 alkenylene). In other embodiments, the alkenylene group comprises two to five carbon atoms (e.g., _C2 - _C5 alkenylene). In other embodiments, the alkenylene group comprises two to four carbon atoms (e.g., _C2 - _C4 alkenylene). In other embodiments, the alkenylene group comprises two to three carbon atoms (e.g., _C2 - _C3 alkenylene). In other embodiments, the alkenylene group contains five to eight carbon atoms (e.g., _C5 - _C8 alkenylene). In other embodiments, the alkenylene group contains two to five carbon atoms (e.g., _C2 - _C5 alkenylene). In other embodiments, the alkenylene group contains three to five carbon atoms (e.g., _C3 - _C5 alkenylene).

"Alkyne" or "alkynyl chain" refers to a straight or branched divalent hydrocarbon chain that links the rest of the molecule to a radical, consists solely of carbon and hydrogen, contains at least one carbon-carbon reference bond, and has two to twelve carbon atoms. The alkynyl chain is linked to the rest of the molecule and to the radical through a single bond. In certain embodiments, the alkynyl group contains two to eight carbon atoms (e.g., _C2 - _C8 alkynyl). In other embodiments, the alkynyl group contains two to five carbon atoms (e.g., _C2 - _C5 alkynyl). In other embodiments, the alkynyl group contains two to four carbon atoms (e.g., _C2 - _C4 alkynyl). In other embodiments, the alkynyl group contains two to three carbon atoms (e.g., _C2 - _C3 alkynyl). In other embodiments, the alkynylene group contains two carbon atoms (e.g., _C2 alkynylene). In other embodiments, the alkynylene group contains five to eight carbon atoms (e.g., _C5 - _C8 alkynylene). In other embodiments, the alkynylene group contains three to five carbon atoms (e.g., _C3 - _C5 alkynylene).

"Heteroalkyl" refers to a straight or branched divalent heteroalkyl chain consisting of heteroatoms such as N, O, and S that connect the rest of the molecule to the radical. Additional heteroatoms may also be applicable, including but not limited to B, Al, Si, and P. The heteroalkyl chain is attached to the rest of the molecule and to the radical via a single bond. In some embodiments, the heteroalkyl group comprises one heteroatom. In some embodiments, the heteroalkyl group comprises two heteroatoms. In some embodiments, the heteroalkyl group comprises three heteroatoms. In some embodiments, the heteroalkyl group comprises four heteroatoms. In some embodiments, the heteroalkyl group comprises five heteroatoms. In some embodiments, the impurity atom may be N, O, S, Si or P or a combination thereof. In some embodiments, the impurity atom may be N, O or S or a combination thereof. In some embodiments, the impurity atom may be N, O or a combination thereof.

The term " _Cx-y " or " _Cx - _Cy " when used in conjunction with a chemical moiety such as an alkyl, _alkenyl or alkynyl group is intended to include groups containing x to y carbons in the chain. For example, the term _{" C1-6} alkyl" refers to a substituted or unsubstituted saturated alkyl group containing 1 to 6 carbons, including straight chain alkyl groups and branched chain alkyl groups.

The terms "C _xy alkenyl" and "C _xy alkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups similar in length and possible substitution to the alkyl groups described above, but containing at least one double bond or triple bond, respectively.

As used herein, the term "carbocycle" refers to a saturated, unsaturated or aromatic ring, wherein each atom of the ring is a carbon atom. Carbocycles include 3 to 10-membered monocyclic rings, 5 to 12-membered bicyclic rings, 5 to 12-membered spirobicyclic rings, and 5 to 12-membered bridged rings. Each ring of the bicyclic carbocycle can be selected from saturated, unsaturated and aromatic rings. In exemplary embodiments, an aromatic ring (e.g., phenyl) can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Where valence permits, bicyclic carbocycles include any combination of saturated bicyclic rings, unsaturated bicyclic rings, and aromatic bicyclic rings. Bicyclic carbocycles further include spirobicycles such as spiropentanes. Bicyclic carbocycles include any combination of ring sizes such as 3-3 spiro systems, 4-4 spiro systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, dihydroindenyl, naphthyl, and bicyclo[1.1.1]pentyl.

The term "aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon ring system. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon and five to eighteen carbon atoms, wherein at least one ring of the ring system is aromatic, i.e., contains a cyclic, delocalized (4n+2) π electron system according to the Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, radicals such as benzene, fluorene, indane, indene, tetrahydronaphthalene and naphthalene.

The term "cycloalkyl" refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl groups may include monocyclic and polycyclic rings, such as 3 to 10 membered monocyclic rings, 5 to 12 membered bicyclic rings, 5 to 12 membered spirobicyclic rings, and 5 to 12 membered bridged rings. In certain embodiments, the cycloalkyl group contains three to ten carbon atoms. In other embodiments, the cycloalkyl group contains five to seven carbon atoms. The cycloalkyl group may be connected to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, spiropentanyl, norbornyl (ie, bicyclo[2.2.1]heptyl), decahydronaphthyl, 7,7-dimethylbicyclo[2.2.1]heptyl, bicyclo[1.1.1]pentyl, and the like.

The term "cycloalkenyl" refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyls may include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 5-12 membered bridged rings. In other embodiments, the cycloalkenyl contains five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

The term "halogen" or alternatively "halogen" or "halide" means fluorine, chlorine, bromine or iodine. In some embodiments, the halogen is fluorine, chlorine or bromine.

The term "haloalkyl" refers to an alkyl group as defined above, substituted with one or more halo groups, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the haloalkyl group is optionally further substituted as described herein.

As used herein, the term "heterocyclic" refers to a saturated, unsaturated or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B and S atoms. Heterocyclic rings include 3 to 10-membered monocyclic rings, 6 to 12-membered bicyclic rings, 5 to 12-membered spirobicyclic rings and 5 to 12-membered bridged rings. Monocyclic heterocyclic rings include any saturated, unsaturated and aromatic rings where valence permits. Monocyclic heterocyclic rings include, but are not limited to, oxadiazine, aziridin, furan, tetrahydrofuran, pyrrole, pyrrolidine, pyran, piperidine, piperidine, imidazole, thiazole, morpholine, pyridine, and pyrimidine. Bicyclic heterocyclic rings include any combination of saturated, unsaturated, and aromatic bicyclic rings, where valence permits. In exemplary embodiments, an aromatic ring (e.g., pyridinyl) may be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene). Bicyclic heterocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Examples of fused ring systems include, but are not limited to, isoindoline, isoquinoline, tetrahydroisoquinoline, 3-azabicyclo[3.1.0]hexane, and 6-oxa-3-azabicyclo[3.1.1]heptane. Bicyclic heterocycles further include spirobicycles, such as 5 to 12 membered spirobicycles, such as, but not limited to, 2-Azaspiro[3.3]heptane, 5-Azaspiro[2.4]heptane, 2-Oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 1-thia-6-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2-thia-6-azaspiro[3.4]octane, 4-Oxa-7-azaspiro[ 2.5]octane, 2-azaspiro[4.4]nonane, 2,7-diazaspiro[4.4]nonane, 2-oxa-6-azaspiro[3.5]nonane, 7-oxa-2-azaspiro[3.5]nonane, 2-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 8-oxa-2-azaspiro[4.5]decane and 2-oxa-7-azaspiro[4.5]decane.

The term "heteroaryl" refers to a radical derived from a 5- to 18-membered aromatic ring radical, comprising two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π electron system according to the Hückel theory. Heteroaryls include fused or bridged ring systems. The heteroatoms in the heteroaryl are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heteroaryl is attached to the rest of the molecule via any ring atom. Examples of heteroaryl groups include, but are not limited to, azobenzene, benzimidazolyl, 1,3-benzodioxacyclopentenyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzodioxacyclohexenyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) ), benzotriazolyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, pyrrolyl, pyrazolyl, pyridinyl, pyridopyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, isoquinolyl, tetrahydroquinolyl, and thiophenyl (i.e., thienyl).

The term "heterocycloalkyl" refers to a saturated ring having carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyl groups may include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, 5-12 membered spirobicyclic rings, and 5-12 membered bridged rings. The heteroatoms in the heterocycloalkyl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heterocycloalkyl group is attached to the remainder of the molecule via any atom of the heterocycloalkyl group, such as any carbon or nitrogen atom of the heterocycloalkyl group, as valence permits. Examples of heterocycloalkyl groups include, but are not limited to, azacyclobutanyl, dioxacyclopentanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxolinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinyl, oxacyclobutanyl, piperidinyl, piperonyl, pyrrolidinyl, pyrazolidinyl, quininyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiophenoyl, 3-azabicyclo[3.1.0]hexane, 2-azaspiro[3.3]heptane, 5-azaspiro[2.4]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 6-oxa-3-azabicyclo[3.1.1 ]heptane, 1-thia-6-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2-thia-6-azaspiro[3.4]octane, 4-oxa-7-azaspiro[2.5]octane, 2-azaspiro[4.4]nonane, 2,7-diazaspiro[4.4]nonane, 2-Oxa-6-azaspiro[3.5]nonane, 7-oxa-2-azaspiro[3.5]nonane, 2-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 8-oxa-2-azaspiro[4.5]decane, 2-oxa-7-azaspiro[4.5]decane and 1,1-dioxo-thiophene.

The term "heterocycloalkenyl" refers to an unsaturated ring having carbon atoms and at least one heteroatom with at least one double bond between two ring carbons. Heterocycloalkenyls do not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyls may include monocyclic and polycyclic rings, such as 3 to 10 membered monocyclic rings, 6 to 12 membered bicyclic rings, and 5 to 12 membered bridged rings. In other embodiments, the heterocycloalkenyl contains five to seven ring atoms. The heterocycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl groups include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisooxazole), thiazoline (dihydrothiazole), isothiazolin (dihydroisothiazole), oxadiazolin (dihydroisothiazole), [0043] The invention also includes dihydrothiazolines (dihydrothiadiazoles), dihydropyridine, tetrahydropyridine, dihydrothiazolidine, tetrahydrothiazolidine, dihydropyrimidine, tetrahydropyrimidine, dihydropyridine, tetrahydropyridine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, thiazolidine, dihydrothiazolidine, and dihydrothiazolidine.

The term "substituted" refers to a moiety having substituents replacing hydrogen on one or more carbon or substitutable heteroatoms (e.g., NH or _NH2 ) of a compound. It is understood that "substitution" or "substituted" includes the implied provisos that such substitution is consistent with the permitted valences of the substituted atom and substituents and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, and the like. In certain embodiments, substituted refers to a moiety having substituents replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with a pendoxy, imino, or thiono group. As used herein, the term "substituted" is intended to include all permissible substituents for organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, spirocyclic and nonspirocyclic, aromatic and nonaromatic substituents of organic compounds. For appropriate organic compounds, the permissible substituents may be one or more and the same or different.

In some embodiments, each substituent can individually include any substituent described herein, for example, a halogen, a hydroxyl, an oxy (=O), a thioketo (=S), a cyano (-CN), a nitro (-NO ₂ ), an imino (=NH), an oxime (=N-OH), a hydrazine (=N-NH ₂ ), -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -OR ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^{a )} )C(O)R ^a , —R ^b —N(R ^a )S(O) _t R ^a (wherein t is 1 or 2), —R ^b —S(O) _t R ^a (wherein t is 1 or 2), —R ^b —S(O) _t OR ^a (wherein t is 1 or 2), and —R ^b —S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be substituted as appropriate by alkyl, alkenyl, alkynyl, halogen, halogenalkyl, halogenalkenyl, halogenalkynyl, oxo (═O), thioketo (═S), cyano (—CN), nitro (—NO ₂ -R b -OR a , _-R ^b -OC ⁽ O)-R a , -R ^b -OC(O)-OR ^a , -R b -OC(O)-N(R a ) 2 , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C( ^O )OR ^a , -R ^b -C(O)N(R ^{a ) 2 , -R b -OR c -C(O)N(R a} ₎ ^{2 , -R} _b ^-N (R ^a )C( ^O )OR ^a , -R ^b -N(R ^a )C(O) _R ^{a ,} -R ^{b -N} (R ^a )S(O) _t R ^a (wherein t is 1 or 2), -R ^b -S(O) _t R ^a (wherein t is 1 or 2), -R ^b -S(O) _tORa (wherein t is 1 or 2) and ^-Rb -S(O) _tN ( ^Ra ) ₂ (wherein ^t is 1 or 2); wherein each ^Ra is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, wherein each ^Ra may be substituted, when valence permits, with alkyl, alkenyl, alkynyl, halogen, halogenalkyl, halogenalkenyl, halogenalkynyl, oxo (=O), thioketo (=S), cyano (-CN), nitro ( _-NO2 ), imino (=NH), oxime (=N-OH), hydrazide (=N- _NH2 ), ^{-Rb- ORa} , -Rb ^- OC(O) ^-Ra , -Rb ^- OC(O) ^-ORa -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -OR ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (wherein t is 1 or 2), -R ^b -S(O) _t R ^a (wherein t is 1 or 2), -R ^b -S(O) _t OR ^a (wherein t is 1 or 2), and -R ^b -S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2); and wherein each R ^b is independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, and each R ^c is a straight or branched alkylene, alkenylene or alkynylene chain.

Double bonds to oxygen atoms (such as pendant oxy groups) are represented herein as both "=O" and "(O)". Double bonds to nitrogen atoms are represented herein as both "=NR" and "(NR)". Double bonds to sulfur atoms are represented herein as both "=S" and "(S)".

As used herein, the phrase "parenteral administration" or "administered parenterally" means modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnical, intraspinal, and intrasternal injection and infusion.

The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil and cottonseed oil. , safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solutions; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, citric acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

As used herein, "treatment" or "treating" refers to an approach to obtaining a beneficial or desired result (including but not limited to a therapeutic benefit and/or a preventive benefit) with respect to a disease, disorder, or medical condition. A therapeutic benefit may include, for example, eradication or alleviation of the underlying disorder being treated. Additionally, a therapeutic benefit may include, for example, eradication or alleviation of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual may still be suffering from the underlying disorder. In certain embodiments, for preventive benefit, the composition is administered to an individual at risk for developing a particular disease, or to an individual reporting one or more physiological symptoms of a disease, even though the disease may not have been diagnosed. Treatment by administration of the compounds described herein does not require the involvement of a medical professional. Abbreviation table ACN、MeCN Acetonitrile ℃ Celsius BOC tert-butyloxycarbonyl Cmpd Compound DCM Dichloromethane DIEA or DIPEA Diisopropylethylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide EA, ETOAc, ETAC Ethyl acetate EDC, EDAC or EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI Electrospray Ionization HATU Nitrogen-doped benzotriazole tetramethyluronium hexafluorophosphate HOB Hydroxybenzotriazole HPLC HPLC IC ₅₀ Half minimum (50%) inhibition concentration LCMS LC-MS analysis [M+H+]+ or (MH)+ Mass peak hydrogenation [MH-]- or (MH)- Mass peak subtraction Me methyl MeOH Methanol MS Mass spectrometry analysis N Equivalent PE Petroleum ether PMB (4-methoxyphenyl)methylamine or p-methoxybenzyl Preparative TLC Preparative TLC PyBroP Tris(pyrrolidino)phosphonium hexafluorophosphate bromide RP Reverse RP-HPLC Reverse Phase High Pressure Liquid Chromatography RT or rt Room temperature TLC Thin layer chromatography THF Tetrahydrofuran TFA Trifluoroacetate Compound

The following is a discussion of compounds and salts thereof that can be used in the methods of the present invention. In certain embodiments, the compounds and salts are described by formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) and (IEE).

In one aspect, disclosed herein is a compound represented by formula (I): wherein A is a ring selected from the following: an optionally substituted carbon ring, an optionally substituted 4- to 6-membered heterocyclic ring, and an optionally substituted isoindoline; each of Z ¹ , Z ² , and Y ¹ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)-, and -S(O) ₂ -; each of a and b is independently selected from 1, 2, 3, and 4; each R ¹ is independently selected from halogen, -CN, -NO ₂ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic ring and optionally substituted heterocyclic ring; m is selected from 0 to 5; each R ² is independently selected from hydrogen, halogen, -CN, -OH, -OC _{1 - 4} alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R ² and R ³ substituents are combined to form an optionally substituted heterocyclic ring; each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _{3 -} ^R4 is selected from _hydrogen , halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle and optionally substituted _3-4 membered heterocycloalkyl; each of ^R5 and ^R6 is independently selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle _and optionally substituted _3-4 membered heterocycloalkyl; and ^R7 is selected from hydrogen and optionally substituted _C1-4 alkyl, and wherein if A is optionally substituted _phenyl , _{then m} is ₁ to 5 _and at _least one ^R1 is _{heterocycloalkyl} , wherein if A is an optionally substituted pyridine or an optionally substituted pyrimidine, R ⁴ is selected from hydrogen, a halogen and -CN, and wherein if A is an optionally substituted piperidinesulfonamide, (i) Y ¹ is -C(R ² ) ₂ - and the two R ² substituents are combined to form a ring selected from an optionally substituted heterocycle and an optionally substituted carbocycle, or (ii) R ⁴ is selected from hydrogen, a halogen and -CN.

Ring A can be any suitable ring known to those skilled in the art. In some embodiments, A is a ring selected from the following: an optionally substituted carbocyclic ring, an optionally substituted 4-10 membered heterocyclic ring, and an optionally substituted isoindoline. In some embodiments, A is a ring selected from the following: an optionally substituted carbocyclic ring, an optionally substituted 4-8 membered heterocyclic ring, and an optionally substituted isoindoline. In some embodiments, A is a ring selected from the following: an optionally substituted carbocyclic ring, an optionally substituted 4-6 membered heterocyclic ring, and an optionally substituted isoindoline. In some embodiments, A is selected from optionally substituted azacyclobutane, optionally substituted piperidine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted phenyl, optionally substituted pyridine, optionally substituted pyrazole, optionally substituted isoindoline, and optionally substituted tetrahydroisoquinoline. In some embodiments, A is selected from optionally substituted pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted azacyclobutane, and optionally substituted tetrahydroisoquinoline. In some embodiments, A is not optionally substituted pyridine. In some embodiments, A is not an optionally substituted pyrimidine.

In some embodiments, A is substituted with methyl, -SO ₂ Me, methylpiperidine, methylpiperidinium, methylazaspiro[3.3]heptane, methyldiazaspiro[3.3]heptane, or a combination thereof. In some embodiments, A is substituted with methyl, -SO ₂ Me, -SO ₂ Me, methylpiperidine, methylpiperidinium, or a combination thereof. In some embodiments, A is substituted with methyl, -SO ₂ Me, or a combination thereof. In some embodiments, A is substituted with -SO ₂ Me.

^Z1 and ^Z2 can be any suitable functional group known to those skilled in the art. In some embodiments, ^Z1 and ^Z2 are independently selected from -C( ^R2 ) _2- , -C(O)-, ^-NR3- , -N(C(O) ^R2 )-, -NS( _O2 ) ^R2 , -O-, -S-, -S(O)-, and -S(O) _2- . In some embodiments, ^Z1 and ^Z2 are independently selected from -C( ^R2 ) _2- , -C(O)-, ^-NR3- , -NS( _O2 ) ^R2- , -O-, and -S-. In some embodiments, ^Z1 and ^Z2 are independently selected from -C( ^R2 ) _2- , ^-NR3- , -O-, and -S-. In some embodiments, Z ¹ and Z ² are independently -C(R ² ) ₂ -.

The variables a and b can be any suitable values known to those skilled in the art. In some embodiments, each of a and b is independently selected from 1, 2, 3, and 4. In some embodiments, each of a and b is independently 1, 2, and 3. In some embodiments, each of a and b is independently selected from 1 and 2.

^Y1 can be any suitable functional group known to those skilled in the art. In some embodiments, ^Y1 is selected from -C( ^R2 ) _2- , -C(O)-, ^-NR3- , -N(C(O) ^R2 )-, -NS( _O2 ) ^R2 , -O-, -S-, -S(O)-, and -S(O) _2- . In some embodiments, ^Y1 is selected from -C( ^R2 ) _2- , -C(O)-, ^-NR3- , -NS( _O2 )R2-, -O-, and -S-. In some embodiments, Y1 is selected from -C( ^R2 )2-, -NR3-, -O-, and -S-. In some embodiments, ^Y1 is selected from -C(R2) _2- , ^-NR3- , -O- _, and -S-. In some embodiments, ^Y1 is selected from -C( ^R2 ) ^2- and ^-NR3 . In some embodiments, ^Y1 is -C( ^R2 ) _2- and two ^R2 substituents are combined to form a ring selected from: an optionally substituted heterocyclic ring and an optionally substituted carbocyclic ring. In some embodiments, ^Y1 is -C( ^R2 ) _2- and two ^R2 substituents are combined to form a ring selected from: an optionally substituted heterocyclic ring.

In some embodiments, the compound described as The N-containing heterocyclic ring is selected from an optionally substituted azacyclobutane, an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted piperidine, an optionally substituted morpholine, an optionally substituted tetrahydrothienopyrrole dioxide, and an optionally substituted dihydroindole. In some embodiments, the compound depicted as in formula (I) The N-containing heterocyclic ring system is selected from .

The variable m can be any suitable value known to those skilled in the art. In some embodiments, m is selected from 0 to 5. In some embodiments, m is selected from 0 to 3. In some embodiments, m is selected from 0 to 2. In some embodiments, m is selected from 0 to 1. In some embodiments, m is selected from 1 to 5. In some embodiments, m is selected from 1 to 3. In some embodiments, m is selected from 1 to 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

R ¹ can be any suitable functional group known to those skilled in the art. In some embodiments, each R ¹ is independently selected from halogen, -CN, -NO ₂ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic ring, and optionally substituted heterocyclic ring. In some embodiments, each R ¹ is independently selected from optionally substituted alkyl, optionally substituted carbocyclic ring, and optionally substituted heterocyclic ring. In some embodiments, each R ¹ is independently selected from optionally substituted alkyl and optionally substituted heterocyclic ring. In some embodiments, each R ¹ is independently selected from methyl, optionally substituted piperidine, optionally substituted piperidine, optionally substituted azaspiro[3.3]heptane, and optionally substituted diazaspiro[3.3]heptane. In some embodiments, each R ¹ is independently selected from methyl, ethyl, and optionally substituted diazaspiro[3.3]heptane.

^R2 can be any suitable functional group known to those skilled in the art. In some embodiments, each ^R2 is independently selected from hydrogen, halogen, -CN, -OH, _-OC1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R2 substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle, or ^R2 and ^R3 substituents are combined to form an optionally substituted heterocycle. In some embodiments, each ^R2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, each R is independently selected from hydrogen, fluorine, chlorine, bromine, -CN, cyclopropyl, cyclobutyl, oxadiazine, and azidocyclobutane. In some embodiments, ^each R is independently selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted heterocyclobutane. In some embodiments, ^each R is independently selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted heterocyclobutane. In some embodiments, ^each R is selected from hydrogen, fluorine, -CN, and cyclopropyl. In some embodiments, each R ² is selected from hydrogen, -CN, and cyclopropyl.

In some embodiments, or two ^R2 substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted heterocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted carbocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted carbocyclic ring. Structure .

Each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. Each of Z ¹ and Z ² can be any functional group as previously described.

In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O-, and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond.

The variables a, b, c, and d can be any suitable values known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

In some embodiments, each ^R is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ² is independently selected from hydrogen, fluorine, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

R ³ can be any suitable functional group known to those skilled in the art. In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl, or R ² and R ³ substituents are combined to form an optionally substituted heterocycle. In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxacyclobutane, and optionally substituted azocyclobutane. ^{In some embodiments, each R 3 is selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl} .

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

R ⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-2 alkyl, and optionally substituted C _3-4 carbocycle. In some embodiments, R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl. In some embodiments, R ⁴ is selected from hydrogen, methyl and -CHF _2. In some embodiments, R ⁴ is selected from hydrogen, halogen and -CN. In some embodiments, R ⁴ is selected from hydrogen. In some embodiments, R ⁴ is not optionally substituted phenyl. In some embodiments, R ⁴ is not optionally substituted alkyl.

R ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, R ⁵ is selected from hydrogen and fluorine.

^R6 can be any suitable functional group known to those skilled in the art. In some embodiments, ^R6 is selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R6 is selected from hydrogen, halogen, and optionally substituted _C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, and optionally substituted C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, ^R6 is selected from hydrogen and fluorine. In some embodiments, ^R6 is hydrogen.

R ⁷ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁷ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁷ is selected from hydrogen, methyl, ethyl and propyl. In some embodiments, R ⁷ is hydrogen.

In some embodiments, the compound or its pharmaceutically acceptable salt or solvent complex has the structure of formula (IA): wherein R ⁸ is selected _{from halogen, -CN and optionally substituted C 1-4 alkyl; R 9 is selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle} ^and _{3 to 6} membered heterocycloalkyl; and n is selected from 0 to 9; wherein (i) Y ¹ is -C(R ² ) ₂ - and two R ² substituents are combined to form a ring selected from: optionally substituted heterocycle and optionally substituted carbocycle, or (ii) R ⁴ is selected from hydrogen, halogen and -CN.

In some embodiments, or two ^R2 substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted heterocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted carbocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted carbocyclic ring. Structure .

Each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. Each of Z ¹ and Z ² can be any functional group as previously described.

In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O-, and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond.

The variables a, b, c, and d can be any suitable values known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

In some embodiments, each ^R is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ² is independently selected from hydrogen, fluorine, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

R ⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-2 alkyl, and optionally substituted C _3-4 carbocycle. In some embodiments, R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl. In some embodiments, R ⁴ is selected from hydrogen, methyl and -CHF _2. In some embodiments, R ⁴ is selected from hydrogen, halogen and -CN. In some embodiments, R ⁴ is selected from hydrogen. In some embodiments, R ⁴ is not optionally substituted phenyl. In some embodiments, R ⁴ is not optionally substituted alkyl.

R ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, R ⁵ is selected from hydrogen and fluorine.

^R6 can be any suitable functional group known to those skilled in the art. In some embodiments, ^R6 is selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R6 is selected from hydrogen, halogen, and optionally substituted _C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, and optionally substituted C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, ^R6 is selected from hydrogen and fluorine. In some embodiments, ^R6 is hydrogen.

R ⁷ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁷ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁷ is selected from hydrogen, methyl, ethyl and propyl. In some embodiments, R ⁷ is hydrogen.

R ⁸ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁸ is selected from halogen, -CN and optionally substituted C _1-4 alkyl. In some embodiments, R ⁸ is selected from halogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁸ is selected from optionally substituted C _1-4 alkyl. In some embodiments, R ⁸ is selected from methyl, ethyl and propyl.

R ⁹ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁹ is selected from optionally substituted C _1-4 alkyl, optionally substituted C _3-6 carbocycle and 3 to 6 membered heterocycloalkyl. In some embodiments, R ⁹ is selected from optionally substituted C _1-4 alkyl and optionally substituted C _3-6 carbocycle. In some embodiments, R ⁹ is selected from optionally substituted C _1-4 alkyl. In some embodiments, R ⁹ is selected from methyl, ethyl and propyl.

The variable n can be any suitable value known to those skilled in the art. In some embodiments, n is selected from 0 to 9. In some embodiments, n is selected from 0 to 5. In some embodiments, n is selected from 0 to 3. In some embodiments, n is selected from 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0.

In some embodiments, the compound or its pharmaceutically acceptable salt or solvent complex has the structure of formula (IAA): wherein R ⁸ is selected from halogen, -CN and optionally substituted C _1-4 alkyl; R ⁹ is selected _{from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle and} 3 to 6 membered heterocycloalkyl; _n is selected from 0 to 9; each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond; and each of a, b, c and d is independently selected from 1, 2, 3 and 4.

Each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. Each of Z ¹ and Z ² can be any functional group as previously described.

In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O-, and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond.

The variables a, b, c, and d can be any suitable values known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

In some embodiments, each ^R is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ² is independently selected from hydrogen, fluorine, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

R ⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-2 alkyl, and optionally substituted C _3-4 carbocycle. In some embodiments, R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl. In some embodiments, R ⁴ is selected from hydrogen, methyl and -CHF _2. In some embodiments, R ⁴ is selected from hydrogen, halogen and -CN. In some embodiments, R ⁴ is selected from hydrogen. In some embodiments, R ⁴ is not optionally substituted phenyl. In some embodiments, R ⁴ is not optionally substituted alkyl.

R ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, R ⁵ is selected from hydrogen and fluorine.

^R6 can be any suitable functional group known to those skilled in the art. In some embodiments, ^R6 is selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R6 is selected from hydrogen, halogen, and optionally substituted _C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, and optionally substituted C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, ^R6 is selected from hydrogen and fluorine. In some embodiments, ^R6 is hydrogen.

R ⁷ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁷ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁷ is selected from hydrogen, methyl, ethyl and propyl. In some embodiments, R ⁷ is hydrogen.

R ⁸ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁸ is selected from halogen, -CN and optionally substituted C _1-4 alkyl. In some embodiments, R ⁸ is selected from halogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁸ is selected from optionally substituted C _1-4 alkyl. In some embodiments, R ⁸ is selected from methyl, ethyl and propyl.

R ⁹ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁹ is selected from optionally substituted C _1-4 alkyl, optionally substituted C _3-6 carbocycle, 3 to 6 membered heterocycloalkyl and optionally substituted C _5-6 heteroaryl. In some embodiments, R ⁹ is selected from optionally substituted C _1-4 alkyl, optionally substituted C _3-6 carbocycle and optionally substituted C _5-6 heteroaryl. In some embodiments, R ⁹ is optionally substituted C _5-6 heteroaryl. In some embodiments, R ⁹ is optionally substituted C ₅ heteroaryl. In some embodiments, R ⁹ is an optionally substituted C ₆ heteroaryl. In some embodiments, R ⁹ is an optionally substituted pyrazole. In some embodiments, R ⁹ is selected from an optionally substituted C _1-4 alkyl and an optionally substituted C _3-6 carbocycle. In some embodiments, R ⁹ is selected from an optionally substituted C _1-4 alkyl. In some embodiments, R ^{9 is selected from a methyl, ethyl and propyl group. In some embodiments, R 9 is} a cyclopropyl, a cyclobutyl, a cyclopentyl or a cyclohexyl. In some embodiments, R ⁹ is a cyclopropyl, a cyclobutyl.

The variable n can be any suitable value known to those skilled in the art. In some embodiments, n is selected from 0 to 9. In some embodiments, n is selected from 0 to 5. In some embodiments, n is selected from 0 to 3. In some embodiments, n is selected from 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0.

In some embodiments, the compound or a pharmaceutically acceptable salt or solvent thereof has the structure of formula (IAAA): wherein R ⁹ is selected from optionally substituted C _1-4 alkyl, optionally substituted C _3-6 carbocycle and 3 to 6 membered heterocycloalkyl.

Each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. Each of Z ¹ and Z ² can be any functional group as previously described.

In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O-, and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond.

The variables a, b, c, and d can be any suitable values known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and ^2. In some embodiments, each R ^is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, ^{each R} is independently selected from hydrogen, fluorine, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

In some embodiments, each ^R is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ² is independently selected from hydrogen, fluorine, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

R ⁹ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁹ is selected from optionally substituted optionally substituted C _3-6 carbocycle and 3 to 6 membered heterocycloalkyl. In some embodiments, R ⁹ is selected from optionally substituted optionally substituted C _3-4 carbocycle and 5 to 6 membered heterocycloalkyl. In some embodiments, R ⁹ is selected from optionally substituted cyclopropyl and optionally substituted pyrazole.

In some embodiments, described as The N-containing heterocyclic system is selected from: .

In some embodiments, the compound or its pharmaceutically acceptable salt or solvent complex has the structure of formula (IB): wherein R ¹⁰ is _an optionally substituted heterocycloalkyl group; R ¹¹ is selected from halogen, -CN and an optionally substituted C _1-4 alkyl group; and p is selected _from 0 to 4.

In some embodiments, or two ^R2 substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted heterocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted carbocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted carbocyclic ring. Structure .

Each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. Each of Z ¹ and Z ² can be any functional group as previously described.

In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O-, and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond.

The variables a, b, c, and d can be any suitable values known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and ^2. In some embodiments, each R ^is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, ^{each R} is independently selected from hydrogen, fluorine, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

In some embodiments, each ^R is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ² is independently selected from hydrogen, fluorine, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

R ⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-2 alkyl, and optionally substituted C _3-4 carbocycle. In some embodiments, R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl. In some embodiments, R ⁴ is selected from hydrogen, methyl and -CHF _2. In some embodiments, R ⁴ is selected from hydrogen, halogen and -CN. In some embodiments, R ⁴ is selected from hydrogen. In some embodiments, R ⁴ is not optionally substituted phenyl. In some embodiments, R ⁴ is not optionally substituted alkyl.

R ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, R ⁵ is selected from hydrogen and fluorine.

^R6 can be any suitable functional group known to those skilled in the art. In some embodiments, ^R6 is selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R6 is selected from hydrogen, halogen, and optionally substituted _C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, and optionally substituted C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, ^R6 is selected from hydrogen and fluorine. In some embodiments, ^R6 is hydrogen.

R ⁷ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁷ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁷ is selected from hydrogen, methyl, ethyl and propyl. In some embodiments, R ⁷ is hydrogen.

The variable n can be any suitable value known to those skilled in the art. In some embodiments, n is selected from 0 to 9. In some embodiments, n is selected from 0 to 5. In some embodiments, n is selected from 0 to 3. In some embodiments, n is selected from 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0.

R ¹⁰ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁰ is an optionally substituted heterocycloalkyl. In some embodiments, R ¹⁰ is selected from optionally substituted piperidine, optionally substituted piperidine and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R ¹⁰ is selected from optionally substituted piperidine and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R ¹⁰ is selected from methyl piperidine and methyl-2,6-diazaspiro[3.3]heptane.

R ¹¹ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹¹ is selected from halogen, -CN and optionally substituted C _1-4 alkyl. In some embodiments, R ¹¹ is selected from halogen and optionally substituted C _1-4 alkyl. In some embodiments, R ¹¹ is selected from optionally substituted C _1-4 alkyl. In some embodiments, R ¹¹ is selected from methyl, ethyl and propyl.

The variable p can be any suitable value known to those skilled in the art. In some embodiments, p is selected from 0 to 4. In some embodiments, p is selected from 0 to 3. In some embodiments, p is selected from 0 to 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0.

In some embodiments, the compound or its pharmaceutically acceptable salt or solvent complex has the structure of formula (IBB): wherein R ¹⁰ is an optionally substituted heterocycloalkyl; R ¹¹ is selected from halogen, -CN and an optionally substituted C _1-4 alkyl; p is selected from 0 to 4; each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ₃ -, _-N (C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond; and each of a, b, c and d is independently selected ^from 1, 2, 3 and 4.

Each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. Each of Z ¹ and Z ² can be any functional group as previously described.

In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O-, and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond.

The variables a, b, c, and d can be any suitable values known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and ^2. In some embodiments, each R ^is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, ^{each R} is independently selected from hydrogen, fluorine, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

In some embodiments, each ^R is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ² is independently selected from hydrogen, fluorine, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

R ⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-2 alkyl, and optionally substituted C _3-4 carbocycle. In some embodiments, R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl. In some embodiments, R ⁴ is selected from hydrogen, methyl and -CHF _2. In some embodiments, R ⁴ is selected from hydrogen, halogen and -CN. In some embodiments, R ⁴ is selected from hydrogen. In some embodiments, R ⁴ is not optionally substituted phenyl. In some embodiments, R ⁴ is not optionally substituted alkyl.

R ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, R ⁵ is selected from hydrogen and fluorine.

^R6 can be any suitable functional group known to those skilled in the art. In some embodiments, ^R6 is selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R6 is selected from hydrogen, halogen, and optionally substituted _C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, and optionally substituted C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, ^R6 is selected from hydrogen and fluorine. In some embodiments, ^R6 is hydrogen.

R ⁷ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁷ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁷ is selected from hydrogen, methyl, ethyl and propyl. In some embodiments, R ⁷ is hydrogen.

The variable n can be any suitable value known to those skilled in the art. In some embodiments, n is selected from 0 to 9. In some embodiments, n is selected from 0 to 5. In some embodiments, n is selected from 0 to 3. In some embodiments, n is selected from 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0.

R ¹⁰ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁰ is an optionally substituted heterocycloalkyl. In some embodiments, R ¹⁰ is selected from optionally substituted piperidine, optionally substituted piperidine and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R ¹⁰ is selected from optionally substituted piperidine and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R ¹⁰ is selected from methyl piperidine and methyl-2,6-diazaspiro[3.3]heptane.

R ¹¹ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹¹ is selected from halogen, -CN and optionally substituted C _1-4 alkyl. In some embodiments, R ¹¹ is selected from halogen and optionally substituted C _1-4 alkyl. In some embodiments, R ¹¹ is selected from optionally substituted C _1-4 alkyl. In some embodiments, R ¹¹ is selected from methyl, ethyl and propyl.

The variable p can be any suitable value known to those skilled in the art. In some embodiments, p is selected from 0 to 4. In some embodiments, p is selected from 0 to 3. In some embodiments, p is selected from 0 to 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0.

In some embodiments, the compound or its pharmaceutically acceptable salt or solvent complex has the structure of formula (IC): wherein R ¹² is selected from optionally substituted heterocycloalkyl and optionally substituted cycloalkyl; or R ¹² and R ¹³ are combined to form an optionally substituted heterocycle; R ¹³ is selected from halogen, -CN and optionally substituted _{C 1-4 alkyl} ; and q is selected from 0 to 2.

In some embodiments, or two ^R2 substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted heterocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted carbocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted carbocyclic ring. Structure .

Each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. Each of Z ¹ and Z ² can be any functional group as previously described.

In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O-, and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond.

The variables a, b, c, and d can be any suitable values known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

In some embodiments, each ^R is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ² is independently selected from hydrogen, fluorine, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

R ⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-2 alkyl, and optionally substituted C _3-4 carbocycle. In some embodiments, R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl. In some embodiments, R ⁴ is selected from hydrogen, methyl and -CHF _2. In some embodiments, R ⁴ is selected from hydrogen, halogen and -CN. In some embodiments, R ⁴ is selected from hydrogen. In some embodiments, R ⁴ is not optionally substituted phenyl. In some embodiments, R ⁴ is not optionally substituted alkyl.

R ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, R ⁵ is selected from hydrogen and fluorine.

^R6 can be any suitable functional group known to those skilled in the art. In some embodiments, ^R6 is selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R6 is selected from hydrogen, halogen, and optionally substituted _C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, and optionally substituted C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, ^R6 is selected from hydrogen and fluorine. In some embodiments, ^R6 is hydrogen.

R ⁷ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁷ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁷ is selected from hydrogen, methyl, ethyl and propyl. In some embodiments, R ⁷ is hydrogen.

R ¹² can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹² is an optionally substituted heterocycloalkyl; or R ¹² and R ¹³ are combined to form an optionally substituted heterocycle. In some embodiments, R ¹² is an optionally substituted 5-6 membered heterocycle, or R ¹² and R ¹³ are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R ¹² is an optionally substituted 5-6 membered heterocycle. In some embodiments, R ¹² is selected from an optionally substituted piperidine, an optionally substituted piperidine, and an optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R ¹² is selected from optionally substituted piperidine and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R ¹² is selected from methylpiperidinium and methyl-2,6-diazaspiro[3.3]heptane.

R ¹³ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹³ is selected from halogen, -CN and optionally substituted C _1-4 alkyl; or R ¹² and R ¹³ are combined to form an optionally substituted heterocyclic ring. In some embodiments, R ¹³ is selected _from halogen and optionally substituted C _1-4 alkyl. In some embodiments, R ¹³ is selected from methyl _, ethyl and propyl.

In some embodiments, R ¹² and R ¹³ are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, R ¹² and R ¹³ are taken together to form an optionally substituted heterocyclic ring. In some embodiments, R ¹² and R ¹³ are taken together to form Structure .

The variable q can be any value known to those skilled in the art. In some embodiments, q is selected from 0 to 2. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1.

In some embodiments, the compound or its pharmaceutically acceptable salt or solvent complex has the structure of formula (ICC): wherein R ¹² is an optionally substituted heterocycloalkyl; or R ¹² and R ¹³ are taken together to form _an optionally substituted heterocycle; R ¹³ is selected from halogen, -CN and an optionally substituted C _1-4 alkyl; q is selected from 0 _to 2; and each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond; and each of a, b, c and d is independently selected from 1, 2, 3 and 4.

Each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. Each of Z ¹ and Z ² can be any functional group as previously described.

In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O-, and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond.

The variables a, b, c, and d can be any suitable values known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

In some embodiments, each ^R is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ² is independently selected from hydrogen, fluorine, or two R substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

R ⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-2 alkyl, and optionally substituted C _3-4 carbocycle. In some embodiments, R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl. In some embodiments, R ⁴ is selected from hydrogen, methyl and -CHF _2. In some embodiments, R ⁴ is selected from hydrogen, halogen and -CN. In some embodiments, R ⁴ is selected from hydrogen. In some embodiments, R ⁴ is not optionally substituted phenyl. In some embodiments, R ⁴ is not optionally substituted alkyl.

R ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, R ⁵ is selected from hydrogen and fluorine.

^R6 can be any suitable functional group known to those skilled in the art. In some embodiments, ^R6 is selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R6 is selected from hydrogen, halogen, and optionally substituted _C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, and optionally substituted C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, ^R6 is selected from hydrogen and fluorine. In some embodiments, ^R6 is hydrogen.

R ⁷ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁷ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁷ is selected from hydrogen, methyl, ethyl and propyl. In some embodiments, R ⁷ is hydrogen.

R ¹² can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹² is an optionally substituted heterocycloalkyl; or R ¹² and R ¹³ are combined to form an optionally substituted heterocycle. In some embodiments, R ¹² is an optionally substituted 5-6 membered heterocycle, or R ¹² and R ¹³ are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R ¹² is an optionally substituted 5-6 membered heterocycle. In some embodiments, R ¹² is selected from an optionally substituted piperidine, an optionally substituted piperidine, and an optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R ¹² is selected from optionally substituted piperidine and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R ¹² is selected from methylpiperidinium and methyl-2,6-diazaspiro[3.3]heptane.

R ¹³ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹³ is selected from halogen, -CN and optionally substituted C _1-4 alkyl; or R ¹² and R ¹³ are combined to form an optionally substituted heterocyclic ring. In some embodiments, R ¹³ is selected _from halogen and optionally substituted C _1-4 alkyl. In some embodiments, R ¹³ is selected from methyl _, ethyl and propyl.

In some embodiments, R ¹² and R ¹³ are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, R ¹² and R ¹³ are taken together to form an optionally substituted heterocyclic ring. In some embodiments, R ¹² and R ¹³ are taken together to form Structure .

The variable q can be any value known to those skilled in the art. In some embodiments, q is selected from 0 to 2. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1.

In some embodiments, the compound or its pharmaceutically acceptable salt or solvent complex has the structure of formula (ID): wherein R ¹⁴ is selected from -SOR ¹⁶ - and an optionally substituted heterocycloalkyl; R ¹⁵ is selected from hydrogen, halogen, -CN and _an optionally substituted C _1-4 alkyl; and R ¹⁶ is selected from _{an optionally substituted C 1-4 alkyl} , an optionally substituted C _3-6 carbocycle and an optionally substituted 3-6 membered heterocycloalkyl

In some embodiments, or two ^R2 substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted heterocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted carbocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted carbocyclic ring. Structure .

Each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. Each of Z ¹ and Z ² can be any functional group as previously described.

In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O-, and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond.

The variables a, b, c, and d can be any suitable values known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

In some embodiments, each ^R is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ² is independently selected from hydrogen, fluorine, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

R ⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-2 alkyl, and optionally substituted C _3-4 carbocycle. In some embodiments, R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl. In some embodiments, R ⁴ is selected from hydrogen, methyl and -CHF _2. In some embodiments, R ⁴ is selected from hydrogen, halogen and -CN. In some embodiments, R ⁴ is selected from hydrogen. In some embodiments, R ⁴ is not optionally substituted phenyl. In some embodiments, R ⁴ is not optionally substituted alkyl.

R ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, R ⁵ is selected from hydrogen and fluorine.

^R6 can be any suitable functional group known to those skilled in the art. In some embodiments, ^R6 is selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R6 is selected from hydrogen, halogen, and optionally substituted _C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, and optionally substituted C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, ^R6 is selected from hydrogen and fluorine. In some embodiments, ^R6 is hydrogen.

R ⁷ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁷ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁷ is selected from hydrogen, methyl, ethyl and propyl. In some embodiments, R ⁷ is hydrogen.

R ¹⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁴ is selected from -SOR ¹⁶ - and optionally substituted heterocycloalkyl. In some embodiments, R ¹⁴ is -SOR ¹⁶ -. In some embodiments, R ¹⁴ is selected from optionally substituted heterocycloalkyl.

R ¹⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁵ is selected from hydrogen, halogen, -CN and optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁵ is selected from hydrogen, halogen and optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁵ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁵ is hydrogen. In some embodiments, R ¹⁵ is optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁵ is methyl, ethyl and propyl.

R ¹⁶ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁶ is selected from optionally substituted C _1-4 alkyl, optionally substituted C _3-6 carbocycle and optionally substituted 3 to 6 membered heterocycloalkyl. In some embodiments, R ¹⁶ is optionally substituted C _3-6 carbocycle and optionally substituted 3 to 6 membered heterocycloalkyl. In some embodiments, R ¹⁶ is selected from optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁶ is selected from methyl, ethyl and propyl.

In some embodiments, the compound or its pharmaceutically acceptable salt or solvent complex has the structure of formula (IDD): wherein R ¹⁶ is selected from an optionally substituted C _1-4 alkyl group, an optionally substituted C _3-6 carbocycle, and an optionally substituted 3-6 membered heterocycloalkyl group.

Each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. Each of Z ¹ and Z ² can be any functional group as previously described.

In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O-, and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond.

The variables a, b, c, and d can be any suitable values known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

In some embodiments, each ^R is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ² is independently selected from hydrogen, fluorine, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

R ⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-2 alkyl, and optionally substituted C _3-4 carbocycle. In some embodiments, R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl. In some embodiments, R ⁴ is selected from hydrogen, methyl and -CHF _2. In some embodiments, R ⁴ is selected from hydrogen, halogen and -CN. In some embodiments, R ⁴ is selected from hydrogen. In some embodiments, R ⁴ is not optionally substituted phenyl. In some embodiments, R ⁴ is not optionally substituted alkyl.

R ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, R ⁵ is selected from hydrogen and fluorine.

^R6 can be any suitable functional group known to those skilled in the art. In some embodiments, ^R6 is selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R6 is selected from hydrogen, halogen, and optionally substituted _C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, and optionally substituted C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, ^R6 is selected from hydrogen and fluorine. In some embodiments, ^R6 is hydrogen.

R ⁷ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁷ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁷ is selected from hydrogen, methyl, ethyl and propyl. In some embodiments, R ⁷ is hydrogen. R ¹⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁵ is selected from hydrogen, halogen, -CN and optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁵ is selected from hydrogen, halogen and optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁵ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁵ is hydrogen. In some embodiments, R ¹⁵ is optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁵ is methyl, ethyl and propyl.

R ¹⁶ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁶ is selected from optionally substituted C _1-4 alkyl, optionally substituted C _3-6 carbocycle and optionally substituted 3 to 6 membered heterocycloalkyl. In some embodiments, R ¹⁶ is optionally substituted C _3-6 carbocycle and optionally substituted 3 to 6 membered heterocycloalkyl. In some embodiments, R ¹⁶ is selected from optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁶ is selected from methyl, ethyl and propyl.

In some embodiments, the compound or its pharmaceutically acceptable salt or solvent complex has the structure of Formula (IE): wherein R ¹⁷ is selected _from -SOR ¹⁹ -, an optionally substituted alkyl group, an optionally substituted carbocyclic group, and an optionally substituted heterocycloalkyl group; R ¹⁸ is selected from a halogen, -CN, and an optionally substituted C _1-4 alkyl group; R ¹⁹ is selected _{from an} optionally substituted C _1-4 alkyl group, an optionally substituted C _{3-6 carbocyclic} group, and an optionally substituted 3- to 6-membered heterocycloalkyl group; and r is selected _{from 0} to 5.

In some embodiments, or two ^R2 substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted heterocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted carbocyclic ring. In some embodiments, two ^R2 substituents are combined to form an optionally substituted carbocyclic ring. Structure .

Each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. Each of Z ¹ and Z ² can be any functional group as previously described.

In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O-, and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond.

The variables a, b, c, and d can be any suitable values known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

In some embodiments, each ^R is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ² is independently selected from hydrogen, fluorine, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

R ⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-2 alkyl, and optionally substituted C _3-4 carbocycle. In some embodiments, R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl. In some embodiments, R ⁴ is selected from hydrogen, methyl and -CHF _2. In some embodiments, R ⁴ is selected from hydrogen, halogen and -CN. In some embodiments, R ⁴ is selected from hydrogen. In some embodiments, R ⁴ is not optionally substituted phenyl. In some embodiments, R ⁴ is not optionally substituted alkyl.

R ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, R ⁵ is selected from hydrogen and fluorine.

^R6 can be any suitable functional group known to those skilled in the art. In some embodiments, ^R6 is selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R6 is selected from hydrogen, halogen, and optionally substituted _C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, and optionally substituted C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, ^R6 is selected from hydrogen and fluorine. In some embodiments, ^R6 is hydrogen.

R ⁷ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁷ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁷ is selected from hydrogen, methyl, ethyl and propyl. In some embodiments, R ⁷ is hydrogen. R ¹⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁴ is selected from -SOR ¹⁶ - and optionally substituted heterocycloalkyl. In some embodiments, R ¹⁴ is -SOR ¹⁶ -. In some embodiments, R ¹⁴ is selected from optionally substituted heterocycloalkyl.

R ¹⁷ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁷ is selected from -SOR ¹⁹ -, an optionally substituted alkyl group, an optionally substituted carbocyclic group, and an optionally substituted heterocycloalkyl group. In some embodiments, R ¹⁷ is selected from -SOR ¹⁹ -, an optionally substituted alkyl group, and an optionally substituted 3-5 membered heterocycloalkyl group. In some embodiments, R ¹⁷ is selected from -SOR ¹⁹ -, a methyl group, and an optionally substituted 4-membered heterocycloalkyl group. In some embodiments, R ¹⁷ is selected from -SOR ¹⁹ -, a methyl group, and 1-(methylsulfonyl)azinecyclobutane. In some embodiments, R ¹⁷ is -SOR ¹⁹ -. In some embodiments, R ¹⁷ is methyl. In some embodiments, R ¹⁷ is 1-(methylsulfonyl)azetidine.

R ¹⁸ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁸ is selected from halogen, -CN and optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁸ is selected from halogen and optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁸ is selected from optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁸ is selected from methyl, ethyl and propyl.

R ¹⁹ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁹ is selected from optionally substituted C _1-4 alkyl, optionally substituted C _3-6 carbocycle and optionally substituted 3 to 6 membered heterocycloalkyl. In some embodiments, R ¹⁹ is selected from optionally substituted C _3-6 carbocycle and optionally substituted 3 to 6 membered heterocycloalkyl. In some embodiments, R ¹⁹ is optionally substituted alkyl. In some embodiments, R ¹⁹ is selected from methyl, ethyl and propyl. In some embodiments, R ¹⁹ is methyl.

The variable r can be any suitable value known to those skilled in the art. In some embodiments, r is selected from 0 to 5. In some embodiments, r is selected from 0 to 3. In some embodiments, r is selected from 0 to 2. In some embodiments, r is 0 or 1. In some embodiments, r is 0.

In some embodiments, the compound or its pharmaceutically acceptable salt or solvent complex has the structure of formula (IEE): wherein R ¹⁹ is selected from an optionally substituted C _1-4 alkyl group, an optionally substituted C _3-6 carbocycle, and an optionally substituted 3-6 membered heterocycloalkyl group.

Each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. Each of Z ¹ and Z ² can be any functional group as previously described.

In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond. In some embodiments, each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O-, and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond.

The variables a, b, c, and d can be any suitable values known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

In some embodiments, each ^R is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl, or two ^R substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R ² is independently selected from hydrogen, fluorine, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

In some embodiments, each R ^is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, each R ^is independently selected from hydrogen, fluorine, and -OH. In some embodiments, each ^R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, ^R is independently selected from hydrogen and fluorine.

In some embodiments, each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, each R ³ is independently selected from optionally substituted alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ³ is selected from optionally substituted alkyl. In some embodiments, each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, each R ³ is selected from cyclopropyl and cyclobutyl. In some embodiments, R ³ is cyclopropyl.

In some embodiments, R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R ³ is methyl.

R ⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁴ is selected from hydrogen, halogen, -CN, optionally substituted C _1-2 alkyl, and optionally substituted C _3-4 carbocycle. In some embodiments, R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl. In some embodiments, R ⁴ is selected from hydrogen, methyl and -CHF _2. In some embodiments, R ⁴ is selected from hydrogen, halogen and -CN. In some embodiments, R ⁴ is selected from hydrogen. In some embodiments, R ⁴ is not optionally substituted phenyl. In some embodiments, R ⁴ is not optionally substituted alkyl.

R ⁵ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁵ is selected from hydrogen, halogen, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C _3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, halogen, and optionally substituted C _1-2 alkyl. In some embodiments, R ⁵ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, R ⁵ is selected from hydrogen and fluorine.

^R6 can be any suitable functional group known to those skilled in the art. In some embodiments, ^R6 is selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle, and optionally substituted 3-4 membered heterocycloalkyl. In some embodiments, R6 is selected from hydrogen, halogen, and optionally substituted _C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, halogen, and optionally substituted C1-2 alkyl. In some embodiments, ^R6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, and propyl. In some embodiments, ^R6 is selected from hydrogen and fluorine. In some embodiments, ^R6 is hydrogen.

R ⁷ can be any suitable functional group known to those skilled in the art. In some embodiments, R ⁷ is selected from hydrogen and optionally substituted C _1-4 alkyl. In some embodiments, R ⁷ is selected from hydrogen, methyl, ethyl and propyl. In some embodiments, R ⁷ is hydrogen. R ¹⁴ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁴ is selected from -SOR ¹⁶ - and optionally substituted heterocycloalkyl. In some embodiments, R ¹⁴ is -SOR ¹⁶ -. In some embodiments, R ¹⁴ is selected from optionally substituted heterocycloalkyl.

R ¹⁸ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁸ is selected from halogen, -CN and optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁸ is selected from halogen and optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁸ is selected from optionally substituted C _1-4 alkyl. In some embodiments, R ¹⁸ is selected from methyl, ethyl and propyl.

R ¹⁹ can be any suitable functional group known to those skilled in the art. In some embodiments, R ¹⁹ is selected from optionally substituted C _1-4 alkyl, optionally substituted C _3-6 carbocycle and optionally substituted 3 to 6 membered heterocycloalkyl. In some embodiments, R ¹⁹ is selected from optionally substituted C _3-6 carbocycle and optionally substituted 3 to 6 membered heterocycloalkyl. In some embodiments, R ¹⁹ is optionally substituted alkyl. In some embodiments, R ¹⁹ is selected from methyl, ethyl and propyl. In some embodiments, R ¹⁹ is methyl.

The variable r can be any suitable value known to those skilled in the art. In some embodiments, r is selected from 0 to 5. In some embodiments, r is selected from 0 to 3. In some embodiments, r is selected from 0 to 2. In some embodiments, r is 0 or 1. In some embodiments, r is 0.

In some embodiments, the compound is selected from: .

In some embodiments, the compound is selected from: and .

In some embodiments, the compound is selected from: .

In some embodiments, the compound is selected from: .

In some embodiments, the compound is selected from: .

In some embodiments, the compound is selected from: .

Additional embodiments of the compounds of the present invention include the following:

Example 1 relates to a compound or a pharmaceutically acceptable salt or solvent thereof, which has a structure of formula (I): wherein A is a ring selected from the following: an optionally substituted carbon ring, an optionally substituted 4- to 8-membered heterocyclic ring, an optionally substituted tetrahydro-triazolopyridine, and an optionally substituted isoindoline; ^Z0 is -C(H)- or nitrogen; each of ^Z1 , ^Z2 , and ^Y1 is independently selected from -C( ^R2 ) _2- , -C(O)-, ^-NR3-, -N(C(O) ^R2 )-, -NS( _O2 ) ^R2 , -O-, -S-, -S(O)-, and -S(O) _2- ; each of a and b is independently selected from 1, 2, 3, and 4; each ^R1 is independently selected from halogen, -CN, _-NO2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic ring and optionally substituted heterocyclic ring; m is selected from 0 to 5; each R ² is independently selected from hydrogen, halogen, -CN, -OH, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted -O-cycloalkyl and optionally substituted heterocyclic ring, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R ² and R ³ substituents are combined to form an optionally substituted heterocyclic ring; each R ^R3 is independently selected from hydrogen, an optionally substituted alkyl, _an optionally substituted _C3-4 carbocycle, and an optionally substituted _{3-4 membered heterocycloalkyl; R4 is selected from hydrogen, a halogen, -CN, an optionally substituted C1-4} ^alkyl _{, an} optionally substituted _C3-4 carbocycle, and _an optionally substituted _3-4 membered heterocycloalkyl; each of ^R5 and ^R6 is independently selected from hydrogen, a halogen _{, -CN} , _an optionally substituted _C1-4 alkyl, _an optionally substituted _C3-4 carbocycle, and an optionally substituted _3-4 membered heterocycloalkyl; and ^R7 is selected _from hydrogen and an optionally substituted _C1- wherein if A is an optionally substituted phenyl, m is 1 to 5 and at least one R ¹ is a heterocycloalkyl, wherein if A is an optionally substituted pyridine, an optionally substituted pyrimidine or an optionally substituted pyrimidine, R ₄ is selected from hydrogen, a halogen and -CN, wherein if A is an optionally substituted piperidinesulfonamide, (i) Y ¹ is -C(R ² ) ₂ - and the two R ² substituents are combined to form a ring selected from an optionally substituted heterocycle and an optionally substituted carbocycle, or (ii) R ⁴ is selected from hydrogen, a halogen, a methyl and -CN, and wherein if ^{AR 1 is} and Z ⁰ is CH, then R ⁴ is methyl or cyclopropyl.

Example 2 is related to the compound of Example 1 or a pharmaceutically acceptable salt or solvent thereof, which has a structure of formula (I): , wherein A is a ring selected from the following: an optionally substituted carbon ring, an optionally substituted 4- to 6-membered heterocyclic ring, and an optionally substituted isoindoline.

Example 3 is a compound of Example 1 or 2 or a pharmaceutically acceptable salt or solvent thereof, which has a structure of any one of Formula (IA), (IB), (IC), (ID) or (IE): wherein R ⁸ is selected from halogen, -CN and an optionally substituted C _{1 - 4} alkyl; R ⁹ is selected from an optionally substituted C _{3 - 6} carbocyclic ring, an optionally substituted C _{5 - 6} heteroaryl group and a 3- to 6-membered heterocycloalkyl group; R ¹⁰ is an optionally substituted alkyl group or an optionally substituted heterocycloalkyl group; R ¹¹ is selected from halogen, -CN and an optionally substituted C _{1 - 4} alkyl group; R ¹² is selected from an optionally substituted heterocycloalkyl group, an optionally substituted heterocycloalkylalkyl group, an optionally substituted cycloalkyl group and an optionally substituted cycloalkylalkyl group; or R ¹² and R ¹³ are combined to form an optionally substituted heterocyclic ring; R ^{R 13} is selected from halogen, -CN and _an optionally substituted C _{1-4 alkyl} group; n is selected from 0 to 9; R ¹⁴ is selected from -SOR ¹⁶ - and an optionally substituted heterocycloalkyl group; R ¹⁵ is selected from hydrogen, halogen, -CN _{and an optionally substituted C 1-4 alkyl group; R 16 is selected from an optionally substituted C 1-4 alkyl group, an optionally substituted C 3-6 carbocyclic group and an} ^optionally _{substituted 3-6 membered heterocycloalkyl} group; R ¹⁷ is selected from -SOR ¹⁹ -, an optionally substituted alkyl group, an optionally substituted carbocyclic group and an optionally substituted heterocycloalkyl group; R ¹⁸ is selected _from halogen, -CN and _an optionally substituted C _1-4 alkyl group; R ¹⁹ is selected from _{optionally substituted C 1-4 alkyl , optionally substituted C 3-6 carbocycle and} optionally substituted 3-6 membered heterocycloalkyl; r is selected from 0 to 5; p is selected from 0 to 4; q is selected from 0 to 2; and wherein when the compound has formula (IA), (i) Y ¹ is -C(R ² ) ₂ - and the two R ² substituents are combined to form a ring selected from: optionally substituted heterocycle and optionally substituted carbocycle, or (ii) R ⁴ is selected from hydrogen, halogen and -CN.

Example 4 relates to the compound of Example 3 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IA).

Example 5 relates to the compound of Example 3 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IB).

Example 6 relates to the compound of Example 3 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IC).

Example 7 relates to the compound of Example 3 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IE).

Embodiment 8 relates to a compound according to any one of Embodiments 1-7 or a pharmaceutically acceptable salt or solvent thereof, wherein ^Z1 and ^Z2 are independently selected from -C( ^R2 ) _2- , ^-NR3- , -O- and -S-.

Embodiment 9 relates to the compound of Embodiment 8 or a pharmaceutically acceptable salt or solvent thereof, wherein Z ¹ and Z ² are independently -C(R ² ) ₂ -.

Embodiment 10 relates to the compound of Embodiment 9 or a pharmaceutically acceptable salt or solvent thereof, wherein each of a and b is independently selected from 1 and 2.

Embodiment 11 relates to the compound of any one of Embodiments 1-10 or a pharmaceutically acceptable salt or solvent thereof, wherein Y ¹ is selected from -C(R ² ) ₂ -, -NR ³ -, -NS(O ₂ )R ² , -O-, -S(O) ₂ - and -S-.

Embodiment 12 relates to the compound of Embodiment 11 or a pharmaceutically acceptable salt or solvent thereof, wherein Y ¹ is selected from -C(R ² ) ₂ - and -NR ³ .

Embodiment 13 relates to a compound according to any one of Embodiments 1-12 or a pharmaceutically acceptable salt or solvent thereof, wherein each R ² is independently selected from hydrogen, OH, halogen, -CN, optionally substituted alkyl, optionally substituted -O-alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl.

Embodiment 14 relates to the compound of Embodiment 13 or a pharmaceutically acceptable salt or solvent thereof, wherein each R ² is independently selected from hydrogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl.

Embodiment 15 relates to the compound of Embodiment 14 or a pharmaceutically acceptable salt or solvent thereof, wherein each R ² is independently selected from hydrogen, -CN and cyclopropyl.

Embodiment 16 relates to a compound according to any one of Embodiments 1-15 or a pharmaceutically acceptable salt or solvent thereof, wherein two ^R2 substituents are combined together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

Embodiment 17 relates to a compound according to any one of Embodiments 1-16 or a pharmaceutically acceptable salt or solvent thereof, wherein each R ³ is selected from fluorine, optionally substituted alkyl, cyclopropyl, cyclobutyl, optionally substituted oxacyclobutane and optionally substituted azacyclobutane.

Example 18 relates to the compound of Example 17 or a pharmaceutically acceptable salt or solvent thereof, wherein each R ³ is selected from methyl, methoxyethyl, CD ₃ , cyclopropyl and cyclobutyl.

Example 19 relates to the compound of Example 18 or a pharmaceutically acceptable salt or solvent thereof, wherein R ³ is cyclopropyl.

Example 20 relates to a compound of Example 1-3 or a pharmaceutically acceptable salt or solvent thereof, which has a structure of any one of Formula (IAA), (IBB), (ICC), (IDD) or (IEE): wherein R ⁸ is selected from halogen, -CN and an optionally substituted C _{1 - 4} alkyl group; R ⁹ is selected from an optionally substituted C _{3 - 6} carbocyclic ring, an optionally substituted C _{5 - 6} heteroaryl group and a 3- to 6-membered heterocycloalkyl group; R ¹⁰ is an optionally substituted heterocycloalkyl group; R ¹¹ is selected from halogen, -CN and an optionally substituted C _{1 - 4} alkyl group; R ¹² is an optionally substituted heterocycloalkyl group; or R ¹² and R ¹³ are combined to form an optionally substituted heterocyclic ring; R ¹³ is selected from halogen, -CN and an optionally substituted C _{1 - 4} alkyl group; R ^R15 is selected from hydrogen, _halogen , -CN and optionally substituted _C1-4 alkyl; ^R16 is selected from optionally substituted _C1-4 alkyl, optionally substituted _{C3-6 carbocyclic} ring and optionally substituted _3-6 membered heterocycloalkyl _; ^R19 is selected from optionally substituted _C1-4 alkyl, optionally substituted _{C3-6 carbocyclic} ring and optionally substituted _3-6 membered heterocycloalkyl; n is selected from 0 _{to 9 ;} p is selected from 0 to 4; q is selected _from 0 to 2; each of ^Z1 , ^Z2 , ^Z3 , ^Z4 and ^Z5 is independently selected from -C( ^R2 ) _2- , -C(O)-, ^-NR3- , -N(C(O) ^R2 )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)-, and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond; and each of a, b, c, and d is independently selected from 1, 2, 3, and 4.

Example 21 relates to the compound of Example 20 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IAA).

Example 22 relates to the compound of Example 20 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IBB).

Example 23 relates to the compound of Example 20 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (ICC).

Example 24 relates to the compound of Example 20 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IEE).

Embodiment 25 relates to a compound according to any one of Embodiments 16-24 or a pharmaceutically acceptable salt or solvent thereof, wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond.

Example 26 relates to the compound of Example 25 or a pharmaceutically acceptable salt or solvent thereof, wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -O- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond.

Embodiment 27 relates to a compound as described in any one of Embodiments 16-26 , or a pharmaceutically acceptable salt or solvent thereof, wherein each R ² is independently selected from hydrogen, halogen, -CN, OH, an optionally substituted alkyl, an optionally substituted cycloalkyl, and an optionally substituted heterocycloalkyl, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

Example 28 relates to the compound of Example 27 or a pharmaceutically acceptable salt or solvent thereof, wherein each R ² is selected from hydrogen, fluorine, CN, cyclopropyl, cyclobutyl, -C _1-4 alkyl, -C _1-4 halogenalkyl, -OC _1-4 alkyl, -C _1-4 alkylene-OC _1-3 alkyl, -C _1-4 alkylene-OH, optionally substituted oxacyclobutane and optionally substituted azacyclobutane.

Embodiment 29 relates to a compound according to any one of Embodiments 16-28 or a pharmaceutically acceptable salt or solvent thereof, wherein R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, -S(O) ₂ CH ₃ , -C _1-4 alkylene-OC _1-3 alkyl, C _1-4 alkyl, cyclopropyl, cyclobutyl, optionally substituted oxacyclobutane and optionally substituted azacyclobutane.

Example 30 relates to the compound of Example 29 or a pharmaceutically acceptable salt or solvent thereof, wherein R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, C _1-4 alkyl, cyclopropyl, cyclobutyl, optionally substituted oxacyclobutane and optionally substituted azacyclobutane.

Embodiment 31 relates to the compound of Embodiment 30 or a pharmaceutically acceptable salt or solvent thereof, wherein R ³ is selected from hydrogen, methyl, ethyl, propyl, CD ₃ and cyclopropyl.

Embodiment 32 relates to a compound according to any one of Embodiments 16-31 or a pharmaceutically acceptable salt or solvent thereof, wherein each a, b, c and d is independently selected from 1 and 2.

Embodiment 33 relates to the compound of Embodiment 1 or 2 or a pharmaceutically acceptable salt or solvent thereof, wherein A is selected from optionally substituted cyclohexane, optionally substituted pyridine, optionally substituted piperidine, optionally substituted tetrahydropyran, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted azacyclobutane and optionally substituted tetrahydroisoquinoline.

Example 34 relates to the compound of Example 33 or a pharmaceutically acceptable salt or solvent thereof, wherein A is an optionally substituted piperidine.

Embodiment 35 relates to the compound of Embodiment 34 or a pharmaceutically acceptable salt or solvent thereof, wherein A is substituted by -SO ₂ R ⁹ , wherein R ⁹ is selected from an optionally substituted C _3-6 carbocycle, an optionally substituted C _5-6 heteroaryl and a 3-6 membered heterocycloalkyl.

Embodiment 36 relates to the compound of Embodiment 34 or 35 or a pharmaceutically acceptable salt or solvent thereof, wherein m is selected from 0 to 1.

Embodiment 37 relates to a compound according to any one of Embodiments 34-36 , or a pharmaceutically acceptable salt or solvent thereof, wherein each R ¹ is independently selected from an optionally substituted alkyl, an optionally substituted carbocyclic ring and an optionally substituted heterocyclic ring.

Embodiment 38 relates to the compound of Embodiment 37 or a pharmaceutically acceptable salt or solvent thereof, wherein each R ¹ is independently selected from optionally substituted alkyl and optionally substituted heterocyclic.

Embodiment 39 relates to the compound of Embodiment 37 or a pharmaceutically acceptable salt or solvent thereof, wherein each R ¹ is independently selected from methyl, ethyl and optionally substituted diazaspiro[3.3]heptane.

Embodiment 40 relates to a compound according to any one of Embodiments 1 to 13 and 34 to 39 , or a pharmaceutically acceptable salt or solvent thereof, wherein ^Z1 and ^Z2 are independently selected from -C( ^R2 ) _2- , ^-NR3- , -O- and -S-.

Embodiment 41 relates to the compound of Embodiment 40 or a pharmaceutically acceptable salt or solvent thereof, wherein ^Z1 and ^Z2 are each -C( ^R2 ) _2- .

Embodiment 42 relates to the compound of Embodiment 40 or 41 or a pharmaceutically acceptable salt or solvent thereof, wherein each of a and b is independently selected from 1 and 2.

Embodiment 43 relates to a compound according to any one of Embodiments 1 to 13 and 34 to 42 , or a pharmaceutically acceptable salt or solvent thereof, wherein Y ¹ is selected from -C(R ² ) ₂ -, -NR ³ -, -O- and -S-.

Embodiment 44 relates to the compound of Embodiment 43 or a pharmaceutically acceptable salt or solvent thereof, wherein Y ¹ is selected from -C(R ² ) ₂ - and -NR ³ .

Embodiment 45 relates to the compound of Embodiment 44 or a pharmaceutically acceptable salt or solvent thereof, wherein Y ¹ is -C(R ² ) ₂ -, and two R ² substituents are combined to form a ring selected from the group consisting of an optionally substituted heterocyclic ring and an optionally substituted carbocyclic ring.

Embodiment 46 relates to the compound of Embodiment 46 or a pharmaceutically acceptable salt or solvent thereof, wherein Y ¹ is -C(R ² ) ₂ -, and two R ² substituents are combined to form a ring selected from the group consisting of an optionally substituted heterocyclic ring.

Embodiment 47 relates to a compound as in any one of Embodiments 1-19 and 34-46 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is described as The N-containing heterocyclic ring is selected from an optionally substituted azacyclobutane, an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted piperidine, an optionally substituted morpholine, an optionally substituted tetrahydrothienopyrrole dioxide and an optionally substituted dihydroindole.

Embodiment 48 relates to a compound as in any one of Embodiments 1-19 and 34-46 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is described as one of Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring system is selected from .

Embodiment 48(a) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(b) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(c) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(d) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(e) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(f) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(g) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(h) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(i) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(j) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(k) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(l) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(m) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(n) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(o) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(p) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(q) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(r) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(s) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(t) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(u) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(v) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is .

Embodiment 48(w) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(x) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (I), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(y) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(z) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by Formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(aa) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(ab) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(ac) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48 (ad) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is Example 48(ae) relates to a compound of Example 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(af) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(ag) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(ah) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(ai) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(aj) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(ak) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(al) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 48(am) relates to a compound of Embodiment 48 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE). The N-containing heterocyclic ring is .

Embodiment 49 relates to a compound according to any one of Embodiments 1-32 , 34-48 or 48(a) - 48(aj) or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle and optionally substituted 3 to 4 membered heterocycloalkyl.

Embodiment 50 relates to the compound of Embodiment 49 or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl.

Embodiment 51 relates to the compound of Embodiment 50 or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁴ is selected from hydrogen, methyl and -CHF ₂ .

Embodiment 52 relates to a compound according to any one of Embodiments 1-32 , 34-48 or 48(a) - 48(aj) or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁴ is selected from hydrogen, halogen and -CN.

Embodiment 53 relates to a compound according to any one of Embodiments 1-32 , 34-48 or 48(a)-48(aj) or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁴ is selected from hydrogen.

Embodiment 54 relates to a compound according to any one of Embodiments 1-32 , 34-48 or 48(a)-48(aj) or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁴ is not an optionally substituted phenyl group.

Embodiment 55 relates to a compound according to any one of Embodiments 1-32 , 34-48 or 48(a)-48(aj) or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁴ is not an optionally substituted alkyl group.

Embodiment 56 relates to a compound according to any one of Embodiments 1-32 , 34-39 or 50-55 , or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁵ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle and optionally substituted 3-4 membered heterocycloalkyl.

Embodiment 57 relates to the compound of Embodiment 56 or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁵ is selected from hydrogen, halogen and optionally substituted C _1-2 alkyl.

Embodiment 58 relates to the compound of Embodiment 57 or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁵ is selected from hydrogen and fluorine.

Embodiment 59 relates to a compound according to any one of Embodiments 1-32 , 34-39 or 50-58 , or a pharmaceutically acceptable salt or solvent thereof, wherein ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle and optionally substituted 3-4 membered heterocycloalkyl.

Embodiment 60 relates to the compound of Embodiment 59 or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁶ is selected from hydrogen, halogen and optionally substituted C _1-2 alkyl.

Embodiment 61 relates to the compound of Embodiment 60 or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁶ is hydrogen.

Embodiment 62 relates to a compound according to any one of Embodiments 1-32 , 34-39 or 50-61 , or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁷ is hydrogen.

Embodiment 63 relates to a compound according to any one of Embodiments 3-4 , 8-21 or 25-32 , or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁹ is selected from cyclopentyl, methylcyclopentyl, cyclobutylmethylene, cyclopentylmethylene and n-methylpyrazolyl.

Embodiment 63(a) relates to the compound of Embodiment 63 or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁹ is cyclopentyl.

Embodiment 63(b) relates to the compound of Embodiment 63 or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁹ is methylcyclopentyl.

Embodiment 63(c) relates to the compound of Embodiment 63 or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁹ is cyclobutylmethylene.

Embodiment 63(d) relates to the compound of Embodiment 63 or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁹ is cyclopentylmethylene.

Embodiment 63(e) relates to the compound of Embodiment 63 or a pharmaceutically acceptable salt or solvent thereof, wherein R ⁹ is n-methylpyrazolyl.

Example 64 relates to the compound of Example 1 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is selected from Table 1.

Example 65 relates to the compound of Example 2 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is selected from Table 1.

Example 66 relates to the compound of Example 3 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is selected from Table 1.

Embodiment 66 ( a ) of the present invention relates to the compound of formula (IA) or a pharmaceutically acceptable salt thereof as in Embodiment 66 , which is selected from the compounds in Table 1.

Embodiment 66 ( b ) of the present invention relates to the compound of formula (IB) or a pharmaceutically acceptable salt thereof as in Embodiment 66 , which is selected from the compounds in Table 1.

Embodiment 66 ( c ) of the present invention relates to the compound of formula (IC) or a pharmaceutically acceptable salt thereof as in Embodiment 66 , which is selected from the compounds in Table 1.

Embodiment 66 ( d ) of the present invention relates to the compound of formula (ID) or a pharmaceutically acceptable salt thereof as in Embodiment 66 , which is selected from the compounds in Table 1.

Embodiment 66 ( e ) of the present invention relates to the compound of formula (IE) or a pharmaceutically acceptable salt thereof as in Embodiment 66 , which is selected from the compounds in Table 1.

Example 67 relates to the compound of Example 20 or a pharmaceutically acceptable salt or solvent thereof, wherein the compound is selected from Table 1.

Example 67 ( a ) of the present invention relates to the formula (IAA) or a pharmaceutically acceptable salt thereof as in Example 66 , which is selected from the compounds in Table 1.

Example 67 ( b ) of the present invention relates to the compound of formula (IBB) or a pharmaceutically acceptable salt thereof as in Example 66 , which is selected from the compounds in Table 1.

Embodiment 67 ( c ) of the present invention relates to the formula (ICC) or a pharmaceutically acceptable salt thereof as in Embodiment 66 , which is selected from the compounds in Table 1.

Example 67 ( d ) of the present invention relates to the formula (IDD) or a pharmaceutically acceptable salt thereof as in Example 66 , which is selected from the compounds in Table 1.

Embodiment 67 ( e ) of the present invention relates to the compound of formula (IEE) or its pharmaceutically acceptable salt as in Embodiment 66 , which is selected from the compounds in Table 1.

In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, for example, enriched in ² H, ³ H, ¹¹ C, ¹³ C and/or ¹⁴ C content. In a particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and/or efficacy, thereby increasing the duration of action of the drug.

Unless otherwise stated, compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with ^{a13C- or14C} -enriched carbon are within the scope of this invention.

The compounds of the invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute them. For example, the compounds may be isotopically labeled, such as, for example, deuterium ( ^2H ), tritium ( ^3H ), iodine-125 ( ^125I ), or carbon-14 ( ^14C ). Isotopic substitution with ^2H , ^11C , ^13C , ^14C , ^15C , ^12N , ^13N , ^15N , ^16N , ^16O , ^17O , ^14F , ^15F , ^16F , ^17F , ^18F , ^33S , ^34S , ^35S , ^36S , ^35Cl , ^37Cl , ^79Br , ^81Br , and ^125I isotopic substitution is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

In certain embodiments, some or all of ^the1H atoms of the compounds disclosed herein are replaced ^with2H atoms. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

Deuterium substituted compounds were synthesized using various methods as described in Dean, Dennis C., ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Published in: Curr., Pharm. Des., 2000; 6(10)] 2000 , p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989 , 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981 , 64(1-2), 9-32.

Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Company.

The compounds of the present invention also include crystalline and amorphous forms of the compounds, pharmaceutically acceptable salts, and active metabolites of the compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrates), configurational polymorphs and amorphous forms of the compounds, and mixtures thereof.

The present invention includes salts of the compounds described herein, especially pharmaceutically acceptable salts. The compounds of the present invention have sufficiently acidic functional groups, sufficiently basic functional groups, or both functional groups, and can react with a variety of inorganic bases and any of inorganic and organic acids to form salts. Alternatively, intrinsically charged compounds, such as those with quaternary nitrogen, can form salts with appropriate counter ions, such as halogen ions, such as bromide, chloride or fluoride, especially bromide.

In some cases, the compounds described herein may exist as non-mirror isomers, mirror isomers, or other stereoisomeric forms. The compounds presented herein include all non-mirror isomers, mirror isomers, and diastereomeric forms and appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by formation of non-mirror isomers and separation by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, incorporated herein by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. In some embodiments, active metabolites of these compounds having the same type of activity are also included in the scope of the present invention. In addition, the compounds described herein may exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

In certain embodiments, a compound or a salt of a compound may be a prodrug, for example, where a hydroxyl group in the parent compound is present as an ester or carbonate, or a carboxylic acid present in the parent compound is present as an ester. The term "prodrug" is intended to encompass compounds that are converted to the pharmaceutical agent of the present invention under physiological conditions. One method for preparing a prodrug is to include one or more selected moieties that hydrolyze under physiological conditions to produce the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of a host animal, such as a specific target cell in the host animal. For example, esters or carbonates (e.g., esters of alcohols or carboxylic acids or esters of carbonates and phosphonic acids) are preferred prodrugs of the present invention.

Prodrug forms of the compounds described herein, wherein the prodrug is metabolized in vivo to produce the compounds described herein, are included within the scope of the patent application. In some cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

Prodrugs are often useful because they can be more easily administered than the parent drug in some cases. They may be bioavailable, for example, by oral administration, whereas the parent drug is not. Prodrugs may help enhance the cellular permeability of a compound relative to the parent drug. Prodrugs may also have improved solubility in pharmaceutical compositions relative to the parent drug. Prodrugs may be designed as reversible drug derivatives useful as modulators that promote drug transport to site-specific tissues or increase drug retention inside cells.

In some embodiments, the design of the prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol. , 269:G210-218 (1995); McLoed et al., Gastroenterol , 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics , 47, 103 (1988); Sinkula et al., J. Pharm. Sci ., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems , ACS Symposium Series Vol. 14; and Edward B. Roche, Bioreversible Carriers in Drug Design , American Pharmaceutical Association and Pergamon Press, 1987, all disclosures of which are incorporated herein). According to another embodiment, the present invention provides methods for producing the compounds defined above. The compounds can be synthesized using known techniques. Advantageously, these compounds are preferably synthesized from readily available starting materials.

Synthetic chemical transformations and methods for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 2nd ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser 's Reagents for Organic Synthesis (1994); and L. Paquette , ed., Encyclopedia of Reagents for Organic Synthesis (1995). Therapeutic Applications

The methods of administering a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) discussed herein can be used to treat cancer. In some embodiments, methods of treating a solid tumor are disclosed herein. Examples of cancer include, but are not limited to, ovarian cancer, breast cancer, colon cancer, and brain cancer.

In some embodiments, disclosed herein are methods of treating cancer by administering a compound or a pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE). In some embodiments, disclosed herein are methods of treating cancer comprising administering a pharmaceutical composition described herein to a subject in need thereof. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from ovarian cancer, breast cancer, colon cancer, and brain cancer. In some embodiments, the cancer is ovarian cancer or breast cancer.

In some embodiments, disclosed herein is a method of inhibiting cyclin-dependent kinase (CDK) in a cell by administering a compound or a pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE). In some embodiments, disclosed herein is a method of inhibiting cyclin-dependent kinase (CDK) in a cell with a compound or a pharmaceutically acceptable salt of any one of the compounds described herein or the pharmaceutical compositions described herein.

CDK can be any suitable CDK known to those skilled in the art. In some embodiments, CDK is selected from CDK 2, CDK 4, CDK6 or any combination thereof. In some embodiments, CDK is selected from CDK2, CDK4, CDK6, CDK 2/4, CDK 2/6, CDK 4/6 and CDK 2/4/6. In some embodiments, CDK is selected from CDK 2/4, CDK 2/6, CDK 4/6 and CDK 2/4/6. Other embodiments of the therapeutic application of the present invention include the following: Embodiment 69 is a method for treating cancer, comprising administering to an individual in need thereof a compound or a pharmaceutically acceptable salt thereof as in any of Embodiments 1-67 or any of its sub - embodiments or a pharmaceutical composition as in Embodiment 68 . Embodiment 70 relates to the method of embodiment 69 , wherein the cancer is a solid tumor. Embodiment 71 relates to the method of embodiment 69 or 70 , wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer and brain cancer. Embodiment 72 relates to the method of embodiment 71 , wherein the cancer is ovarian cancer or breast cancer. Embodiment 73 relates to a method of inhibiting a cyclin-dependent kinase (CDK) in a cell using a compound of any one of embodiments 1 to 67 or any subembodiment thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of embodiment 68. Embodiment 74 relates to the method of embodiment 73 , wherein the CDK is selected from CDK 2, CDK 4, CDK6 or any combination thereof. Embodiment 75 is related to the method of embodiment 74 , wherein the CDK is selected from CDK 2/4, CDK 2/6, CDK 4/6 and CDK 2/4/6. Embodiment 76 is related to the method of embodiment 75 , wherein the CDK is CDK 2/4/6. Pharmaceutical Formulations

The compositions and methods described herein may be considered as pharmaceutical compositions for administration to a subject in need thereof. The pharmaceutical composition may comprise at least a compound of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) as described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersants, suspending agents, and/or thickening agents. In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described herein and a pharmaceutically acceptable excipient. In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Pharmaceutical compositions comprising a compound of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) or a pharmaceutically acceptable salt may be formulated using one or more physiologically acceptable carriers including excipients and adjuvants. The formulation may vary depending on the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate may be prepared, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or coating the conjugate. Pharmaceutical compositions may also include the compound, salt or conjugate in free base form or in the form of a pharmaceutically acceptable salt. Other embodiments of the pharmaceutical formulations of the present invention include the following: Embodiment 68 relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of any one of Embodiments 1 to 67 or any sub-embodiments thereof and a pharmaceutically acceptable excipient.

Methods for formulating a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) may include formulating any of the compound, salt or conjugate with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semisolid or liquid composition. Solid compositions may include, for example, powders, tablets, dispersible granules and capsules, and in some embodiments, the solid composition further contains non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers and other pharmaceutically acceptable additives. Alternatively, the compound, salt or conjugate may be lyophilized or in powder form for reconstitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.

The pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) may comprise at least one active ingredient (e.g., a compound, salt or conjugate and other agents). The active ingredient may be encapsulated in microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively) prepared, for example, by coacervation techniques or by interfacial polymerization, in a colloidal drug delivery system (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in a macroemulsion.

The compositions and formulations can be sterilized. Sterilization can be achieved by filtration using sterile filtration.

The composition comprising a compound of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) or a pharmaceutically acceptable salt thereof may be formulated for administration as an injectable. Non-limiting examples of injectable formulations may include sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles, such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. The suspension may also contain a suitable stabilizer. The injection may be formulated for bolus injection or continuous infusion. Alternatively, the composition may be lyophilized or in powder form for reconstitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.

For parenteral administration, the compound of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) or a pharmaceutically acceptable salt thereof can be formulated in a unit dose injectable form (e.g., solution, suspension, emulsion) in combination with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be essentially non-toxic and non-therapeutic. Vehicles can be water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as non-volatile oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle may contain minor amounts of additives, such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

In one embodiment, the invention relates to methods for oral delivery to a subject in need thereof and compositions of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) formulated for oral delivery to a subject in need thereof. In one embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to a subject through a mucosal layer in the oral cavity or esophagus. In another embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to a subject through a mucosal layer in the stomach and/or intestines.

In one embodiment, the composition of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) is provided in a modified release dosage form. Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separation layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. The composition may also include a non-release controlling formulation.

In another embodiment, the composition of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) is provided in an enteric-coated dosage form. Such enteric-coated dosage forms may also include non-release-controlled formulations. In one embodiment, the composition is in the form of enteric-coated granules as controlled-release capsules for oral administration. The composition may further include cellulose, sodium dihydrogen phosphate, hydroxypropyl cellulose, tantalum, lactose, mannitol or sodium lauryl sulfate. In another embodiment, the composition is in the form of enteric-coated agglomerated granules as controlled-release capsules for oral administration. The composition may further comprise glyceryl monostearate 40-50, hydroxypropyl cellulose, tantalum, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc or triethyl citrate.

In another embodiment, the composition of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) is an enteric-coated controlled release tablet for oral administration. The composition may further comprise carnauba wax, crosslinked polyvidone, diacetylated monoglycerides, ethyl cellulose, hydroxypropyl cellulose, talc, sodium stearate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide or yellow iron oxide.

Sustained release formulations comprising a compound of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) or a pharmaceutically acceptable salt may also be prepared. Examples of sustained release formulations may include semipermeable matrices of solid hydrophobic polymers that may contain the compound, salt or conjugate, and such matrices may be in the form of shaped articles such as films or microcapsules. Examples of sustained-release matrices may include polyesters, hydrogels such as poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide, copolymers of L-glutamine and γ-ethyl-L-glutamine ester, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPO ^™ (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

Pharmaceutical formulations comprising a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) can be prepared for storage by mixing the compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient and/or stabilizer. The formulation can be a lyophilized formulation or an aqueous solution. The acceptable carrier, excipient and/or stabilizer can be non-toxic to the recipient at the dosage and concentration used. Acceptable carriers, excipients and/or stabilizers may include buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes; and/or non-ionic surfactants or polyethylene glycols.

In another embodiment, the composition of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) may further comprise calcium stearate, crosslinked polyvinylpyrrolidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide and triethyl citrate.

In another embodiment, the composition of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) is provided in a foaming dosage form. Such foaming dosage forms may also contain a non-release controlling formulation.

In another embodiment, the composition of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) can be provided in a dosage form having at least one component that promotes immediate release of the active agent and at least one component that promotes controlled release of the active agent. In another embodiment, the dosage form may be capable of providing discontinuous release of the compound in the form of at least two continuous pulses separated in time by 0.1 to up to 24 hours. The composition may include one or more release-controlling and non-release-controlling excipients, such as those suitable for destructible semipermeable membranes and as swellable substances.

In another embodiment, the composition of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) is provided in a dosage form for oral administration to a subject, wherein the dosage form comprises one or more pharmaceutically acceptable excipients or carriers, enclosed in an intermediate reaction layer comprising a gastro-resistant polymeric layered material having cation exchange capacity that is partially neutralized with a base and has gastro-resistant outer layer.

In some embodiments, the compositions of (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) provided herein may be in unit dosage form or multiple dosage forms. As used herein, unit dosage form refers to physically discrete units suitable for administration to human or non-human animal subjects and individually encapsulated. Each unit dose may contain a predetermined amount of active ingredient, which is combined with the required pharmaceutical carrier or formulation sufficient to produce the desired therapeutic effect. Examples of unit dosage forms include (but are not limited to) ampoules, syringes, and individually encapsulated tablets and capsules. In some embodiments, unit dosage forms can be administered in fractions or multiples thereof. Multiple dosage forms are multiple identical unit dosage forms packaged in a single container, which can be administered in separate unit dosage forms. Examples of multiple dosage forms include, but are not limited to, vials, tablet or capsule bottles, or pint or gallon bottles. In another embodiment, the multiple dosage forms contain different pharmaceutically active agents.

In some embodiments, the composition of (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) can also be formulated as a modified release dosage form, including immediate release, delayed release, extended release, long-term release, sustained release, pulsed release, controlled release, extended release, accelerated release and fast release, targeted release, programmed release and gastric retention dosage forms. Such dosage forms can be prepared according to known methods and techniques (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126, which is incorporated herein by reference in its entirety). Combination therapy

Combination therapy, such as co-administration of the disclosed compounds with additional active agents as part of a specific treatment regimen, is also contemplated herein to provide a beneficial effect from the combined action of such therapeutic agents. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. The combined administration of such therapeutic agents is typically carried out over a defined period of time (typically hours, days, weeks, months, or years, depending on the combination selected). Combination therapy is intended to encompass administration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time; as well as administration of such therapeutic agents or at least two of the therapeutic agents in a substantially simultaneous manner.

Substantially simultaneous administration is achieved, for example, by administering to a subject a single formulation or composition (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent); or in the form of multiple single formulations (e.g., capsules), one single formulation for each therapeutic agent. Sequential administration or substantially simultaneous administration of each therapeutic agent is achieved by any suitable route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissues. The therapeutic agents are administered by the same route or by different routes. For example, the first therapeutic agent in the selected combination is administered by intravenous injection, and the other therapeutic agents in the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

The components of the combination are administered to the patient simultaneously or sequentially. It is understood that the components are present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered simultaneously or sequentially. Other Embodiments

Embodiment 101. A compound or a pharmaceutically acceptable salt or solvent thereof having a structure of formula (I): wherein A is a ring selected from the following: an optionally substituted carbon ring, an optionally substituted 4- to 6-membered heterocyclic ring, and an optionally substituted isoindoline; each of Z ¹ , Z ² , and Y ¹ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)-, and -S(O) ₂ -; each of a and b is independently selected from 1, 2, 3, and 4; each R ¹ is independently selected from halogen, -CN, -NO ₂ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic ring and optionally substituted heterocyclic ring; m is selected from 0 to 5; each R ² is independently selected from hydrogen, halogen, -CN, -OH, -OC _1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R ² and R ³ substituents are combined to form an optionally substituted heterocyclic ring; each R ³ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C _{3 -} ^R4 is selected from _hydrogen , halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle and optionally substituted _3-4 membered heterocycloalkyl; each of ^R5 and ^R6 is independently selected from hydrogen, halogen, -CN, optionally substituted _C1-4 alkyl, optionally substituted _C3-4 carbocycle _and optionally substituted _3-4 membered heterocycloalkyl; and ^R7 is selected from hydrogen and optionally substituted _C1-4 alkyl, and wherein if A is optionally substituted _phenyl , _{then m} is ₁ to 5 _and at _least one ^R1 is _{heterocycloalkyl} , wherein if A is an optionally substituted pyridine or an optionally substituted pyrimidine, R ⁴ is selected from hydrogen, a halogen and -CN, and wherein if A is an optionally substituted piperidinesulfonamide, (i) Y ¹ is -C(R ² ) ₂ - and the two R ² substituents are combined to form a ring selected from an optionally substituted heterocycle and an optionally substituted carbocycle, or (ii) R ⁴ is selected from hydrogen, a halogen and -CN.

Embodiment 102. The compound of Embodiment 101 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IA): wherein R ⁸ is selected _{from halogen, -CN and optionally substituted C 1-4 alkyl; R 9 is selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle} ^and _{3 to 6} membered heterocycloalkyl; and n is selected from 0 to 9; wherein (i) Y ¹ is -C(R ² ) ₂ - and two R ² substituents are combined to form a ring selected from: optionally substituted heterocycle and optionally substituted carbocycle, or (ii) R ⁴ is selected from hydrogen, halogen and -CN.

Embodiment 103. The compound or salt of Embodiment 1 or 3, wherein Z ¹ and Z ² are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O- and -S-.

Embodiment 104. The compound or salt of Embodiment 4, wherein Z ¹ and Z ² are independently -C(R ² ) ₂ -.

Embodiment 105. The compound or salt of Embodiment 9, wherein each of a and b is independently selected from 1 and 2.

Embodiment 106. The compound or salt of any one of Embodiments 1-10, wherein Y ¹ is selected from -C(R ² ) ₂ -, -NR ³ -, -O- and -S-.

Embodiment 107. The compound or salt of Embodiment 11, wherein Y ¹ is selected from -C(R ² ) ₂ - and -NR ³ .

Embodiment 108. The compound or salt of any one of Embodiments 1-12, wherein each R ² is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

Embodiment 109. The compound or salt of Embodiment 13, wherein each R ² is independently selected from hydrogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

Embodiment 110. The compound of Embodiment 14 or a pharmaceutically acceptable salt or solvent thereof, wherein each R ² is independently selected from hydrogen, -CN and cyclopropyl.

Embodiment 111. The compound or salt of Embodiment 1-15, wherein each R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxacyclobutane and optionally substituted azocyclobutane.

Embodiment 112. The compound or salt of Embodiment 17, wherein each R ³ is selected from cyclopropyl and cyclobutyl.

Embodiment 113. The compound or salt of Embodiment 18, wherein R ³ is cyclopropyl.

Embodiment 114. The compound of Embodiment 1 or 3 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IAA): wherein R ⁸ is selected from halogen, -CN and optionally substituted C _1-4 alkyl; R ⁹ is selected _{from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle and} 3 to 6 membered heterocycloalkyl; _n is selected from 0 to 9; each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond; and each of a, b, c and d is independently selected from 1, 2, 3 and 4.

Embodiment 115. The compound or salt of Embodiment 20, wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond.

Embodiment 116. The compound or salt of Embodiment 21, wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond.

Embodiment 117. The compound or salt of Embodiment [0439], wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -O- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond.

Embodiment 118. The compound or salt of Embodiment 20-26, wherein each R ² is independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R ² substituents are combined to form an optionally substituted heterocycle or an optionally substituted carbocycle.

Embodiment 119. The compound or salt of Embodiment 27, wherein each R ² is selected from hydrogen, fluorine, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

Embodiment 120. The compound or salt of any one of Embodiments 20-28, wherein R ³ is selected from hydrogen, cyclopropyl, cyclobutyl, optionally substituted oxazolobutane, and optionally substituted azocyclobutane.

Embodiment 121. The compound or salt of Embodiment 29, wherein R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, cyclopropyl, cyclobutyl, optionally substituted oxacyclobutane, and optionally substituted azacyclobutane.

Embodiment 122. The compound or salt of Embodiment 30, wherein R ³ is selected from -(CH ₂ ) ₂ OMe and cyclopropyl.

Embodiment 123. The compound or salt of any one of Embodiments 20-31, wherein each of a, b, c and d is independently selected from 1 and 2.

Embodiment 124. A compound or salt according to any one of Embodiments 1-32, wherein the compound is selected from: .

Embodiment 125. A compound or salt according to embodiment [0447], wherein the compound is selected from: .

Embodiment 126. The compound of Embodiment 1 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IB): wherein R ¹⁰ is _an optionally substituted heterocycloalkyl group; R ¹¹ is selected from halogen, -CN and an optionally substituted C _1-4 alkyl group; and p is selected _from 0 to 4.

Embodiment 127. The compound or salt of Embodiment [0449], wherein Z ¹ and Z ² are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O- and -S-.

Embodiment 128. The compound or salt of Embodiment [0450], wherein Z ¹ and Z ² are independently -C(R ² ) ₂ -.

Embodiment 129. The compound or salt of Embodiment [0451], wherein each of a and b is independently selected from 1 and 2.

Embodiment 130. The compound or salt of any one of Embodiments [0449] to [0452], wherein Y ¹ is selected from -C(R ² ) ₂ -, -NR ³ -, -O- and -S-.

Embodiment 131. The compound or salt of Embodiment [0453], wherein Y ¹ is -C(R ² ) ₂ -.

Embodiment 132. The compound or salt of any one of Embodiments [0449] to [0454], wherein each R ² is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

Embodiment 133. The compound or salt of Embodiment [0455], wherein each R ² is independently selected from hydrogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl.

Embodiment 134. The compound or salt of Embodiment [0456], wherein each R ² is independently selected from hydrogen, -CN and cyclopropyl.

Embodiment 135. The compound or salt of any one of Embodiments [0449] to [0457], wherein R ³ is selected from cyclopropyl, cyclobutyl, optionally substituted oxacyclobutane and optionally substituted azocyclobutane.

Embodiment 136. The compound or salt of Embodiment [0458], wherein R ³ is selected from cyclopropyl and cyclobutyl.

Embodiment 137. The compound or salt of Embodiment [0459], wherein R ³ is cyclopropyl.

Embodiment 138. A compound as in Embodiment 1 or [0449] or a pharmaceutically acceptable salt or solvent thereof, which has a structure of formula (IBB): wherein R ¹⁰ is an optionally substituted heterocycloalkyl; R ¹¹ is selected from halogen, -CN and an optionally substituted C _1-4 alkyl; p is selected from 0 to 4; each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ₃ -, _-N (C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond; and each of a, b, c and d is independently selected ^from 1, 2, 3 and 4.

Embodiment 139. The compound or salt of Embodiment [0461], wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond.

Embodiment 140. The compound or salt of Embodiment [0462], wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond.

Embodiment 141. The compound or salt of any one of Embodiments [0461] to [0463], wherein each R ² is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

Embodiment 142. The compound or salt of Embodiment [0464], wherein each R ² is independently selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxadiazine, and optionally substituted azocyclobutane.

Embodiment 143 : A compound or salt of Embodiment [0465], wherein each R ² is independently selected from hydrogen, fluorine, -CN and cyclopropyl.

Embodiment 144. The compound or salt of any one of Embodiments [0461] to [0466], wherein R ³ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxazolobutane and optionally substituted azocyclobutane.

Embodiment 145. The compound or salt of Embodiment [0467], wherein R ³ is selected from hydrogen, methyl, ethyl and propyl.

Embodiment 146. The compound of Embodiment [0468] or a pharmaceutically acceptable salt or solvent thereof, wherein R ³ is methyl.

Embodiment 147. The compound or salt of Embodiments [0461]-[0469], wherein each of a, b, c and d is independently selected from 1 and 2.

Embodiment 148. A compound or salt according to any one of Embodiments [0449] to [0470], wherein the compound is selected from: .

Embodiment 149. The compound of Embodiment 1 or a pharmaceutically acceptable salt or solvent thereof, which has a structure of formula (IC): wherein R ¹² is selected from optionally substituted heterocycloalkyl and optionally substituted cycloalkyl; or R ¹² and R ¹³ are combined to form an optionally substituted heterocycle; R ¹³ is selected from halogen, -CN and optionally substituted _{C 1-4 alkyl} ; and q is selected from 0 to 2.

Embodiment 150. The compound or salt of Embodiment [0472], wherein Z ¹ and Z ² are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O- and -S-.

Embodiment 151. The compound or salt of Embodiment [0473], wherein Z ¹ and Z ² are independently -C(R ² ) ₂ -.

Embodiment 152. The compound or salt of Embodiment [0474], wherein each of a and b is independently selected from 1 and 2.

Embodiment 153. The compound or salt of any one of Embodiments [0472] to [0475], wherein Y ¹ is selected from -C(R ² ) ₂ -, -NR ³ -, -NS(O ₂ )R ² , -O- and -S-.

Embodiment 154. The compound or salt of Embodiment [0476], wherein Y ¹ is selected from -C(R ² ) ₂ -, -NR ³ and -NS(O ₂ )R ² .

Embodiment 155. The compound or salt of any one of Embodiments [0472] to [0477], wherein each R ² is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

Embodiment 156. The compound or salt of Embodiment [0478], wherein each R ² is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl.

Embodiment 157. The compound or salt of Embodiment [0479], wherein each R ² is selected from hydrogen, fluorine, -CN and cyclopropyl.

Embodiment 158. The compound or salt of any one of Embodiments [0472]-[0480], wherein R ³ is selected from optionally substituted alkyl.

Embodiment 159. The compound or salt of Embodiment [0481], wherein R ³ is methyl.

Embodiment 160. A pharmaceutically acceptable salt or a solvent complex thereof having a structure of formula (ICC): wherein R ¹² is an optionally substituted heterocycloalkyl; or R ¹² and R ¹³ are taken together to form _an optionally substituted heterocycle; R ¹³ is selected from halogen, -CN and an optionally substituted C _1-4 alkyl; q is selected from 0 _to 2; and each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ² , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond; and each of a, b, c and d is independently selected from 1, 2, 3 and 4.

Embodiment 161. The compound or salt of Embodiment [0483], wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond.

Embodiment 162. The compound or salt of Embodiment [0484], wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ - and -NS(O ₂ )R ³ , wherein Z ⁵ is additionally selected from a bond.

Embodiment 163. A compound or salt according to any one of Embodiments [0483] to [0485], wherein each R ² is independently selected from hydrogen, halogen, -CN, -OH and optionally substituted alkyl.

Embodiment 164. The compound of Embodiment [0486] or a pharmaceutically acceptable salt or solvent thereof, wherein each R ² is independently selected from hydrogen, fluorine and -OH.

Embodiment 165. The compound or salt of any one of Embodiments [0483]-[0487], wherein R ³ is independently selected from hydrogen and optionally substituted alkyl.

Embodiment 166. The compound or salt of Embodiment [0488], wherein R ³ is independently selected from hydrogen, methyl, ethyl and propyl

Embodiment 167. The compound or salt of Embodiment [0489], wherein R ³ is methyl.

Embodiment 168. The compound or salt of any one of Embodiments [0472] to [0490], wherein R ¹² is an optionally substituted 5- to 6-membered heterocyclic ring, or R ¹² and R ¹³ are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

Embodiment 169. The compound or salt of Embodiment [0491], wherein R ¹² is optionally substituted piperidine, optionally substituted azaspiro[3.3]heptane, or R ¹² and R ¹³ are taken together to form an optionally substituted heterocycle.

Embodiment 170. The compound or salt of any one of Embodiments [0472] to [0492], wherein R ¹³ and R ¹² are taken together to form an optionally substituted heterocyclic ring.

Embodiment 171. A compound or salt according to any one of Embodiments [0472] to [0493], wherein the compound is selected from: .

Embodiment 172. A compound or salt according to Embodiment 1, which has a structure of formula (ID): wherein R ¹⁴ is selected from -SOR ¹⁶ - and an optionally substituted heterocycloalkyl; R ¹⁵ is selected from hydrogen, halogen _{, -CN and an optionally substituted C 1-4 alkyl; and R 16 is selected from an optionally substituted C 1-4 alkyl ,} ^an _optionally substituted C _3-6 carbocycle and an optionally substituted 3-6 membered heterocycloalkyl.

Embodiment 173. A compound as in Embodiment 1 or [0495] or a pharmaceutically acceptable salt or solvent thereof, which has a structure of formula (IDD): wherein R ¹⁶ is selected from an optionally substituted C _1-4 alkyl group, an optionally substituted C _3-6 carbocycle, and an optionally substituted 3-6 membered heterocycloalkyl group.

Embodiment 174. A pharmaceutically acceptable salt or a solvent thereof having a structure of formula (IE): wherein R ¹⁷ is selected _from -SOR ¹⁹ -, an optionally substituted alkyl group, an optionally substituted carbocyclic group, and an optionally substituted heterocycloalkyl group; R ¹⁸ is selected from a halogen, -CN, and an optionally substituted C _1-4 alkyl group; R ¹⁹ is selected _{from an} optionally substituted C _1-4 alkyl group, an optionally substituted C _{3-6 carbocyclic} group, and an optionally substituted 3- to 6-membered heterocycloalkyl group; and r is selected _{from 0} to 5.

Embodiment 175. The compound or salt of Embodiment [0497], wherein Z ¹ and Z ² are independently selected from -C(R ² ) ₂ -, -NR ³ -, -O- and -S-.

Embodiment 176. The compound or salt of Embodiment [0498], wherein Z ¹ and Z ² are independently -C(R ² ) ₂ -.

Embodiment 177. The compound or salt of Embodiment [0499], wherein each of a and b is independently selected from 1 and 2.

Embodiment 178. The compound or salt of any one of Embodiments [0497] to [0500], wherein Y ¹ is selected from -C(R ² ) ₂ -, -NR ³ -, -NS(O ₂ )R ² , -O- and -S(O) ₂ -.

Embodiment 179. The compound or salt of any one of Embodiments [0497] to [0501], wherein each R ² is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

Embodiment 180. The compound or salt of any one of Embodiments [0497] to [0502], wherein R ³ is selected from optionally substituted alkyl.

Embodiment 181. A compound or salt according to any one of Embodiments [0497] to [0503], wherein r is 0.

Embodiment 182. The compound or salt of any one of Embodiments [0497] to [0504], wherein R ¹⁷ is selected from -SOR ¹⁹ -, optionally substituted alkyl, and optionally substituted 3-5 membered heterocycloalkyl.

Embodiment 183. The compound or salt of Embodiment [0505], wherein R ¹⁷ is selected from -SOR ¹⁹ -, methyl and optionally substituted 4-membered heterocycloalkyl.

Embodiment 184. A compound according to Embodiment [0497] or a pharmaceutically acceptable salt or solvent thereof, which has a structure of formula (IEE): wherein R ¹⁹ is selected from an optionally substituted C _1-4 alkyl group, an optionally substituted C _3-6 carbocycle, and an optionally substituted 3-6 membered heterocycloalkyl group.

Embodiment 185. The compound or salt of Embodiment [0507], wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond.

Embodiment 186. The compound or salt of Embodiment [0508], wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -NS(O ₂ )R ³ and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond.

Embodiment 187. The compound or salt of any one of Embodiments [0507]-[0509], wherein each R ² is independently selected from hydrogen, halogen, -CN, -OH and optionally substituted alkyl.

Embodiment 188. The compound or salt of Embodiment [0510], wherein each R ² is independently selected from hydrogen and fluorine.

Embodiment 189. The compound or salt of any one of Embodiments [0507]-[0511], wherein R ³ is optionally substituted alkyl.

Embodiment 190. The compound or salt of Embodiment [0512], wherein R ³ is methyl, ethyl or propyl.

Embodiment 191. The compound or salt of Embodiment [0513], wherein R ³ is methyl.

Embodiment 192. The compound or salt of any one of Embodiments [0507]-[0504], wherein R ¹⁹ is optionally substituted alkyl.

Embodiment 193. The compound or salt of Embodiment [0515], wherein R ¹⁹ is methyl.

Embodiment 194. A compound or salt according to any one of Embodiments [0497] to [0516], wherein the compound is selected from: .

Embodiment 195. The compound or salt of Embodiment 1, wherein A is selected from optionally substituted pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted azacyclobutane and optionally substituted tetrahydroisoquinoline.

Embodiment 196. The compound or salt of Embodiment 33, wherein A is substituted with -SO ₂ Me.

Embodiment 197. The compound or salt of Embodiment 33 or 35, wherein m is selected from 0 to 1.

Embodiment 198. The compound or salt of any one of Embodiments 33-36, wherein each R ¹ is independently selected from optionally substituted alkyl, optionally substituted carbocyclic and optionally substituted heterocyclic.

Embodiment 199. The compound or salt of Embodiment 37, wherein each R ¹ is independently selected from optionally substituted alkyl and optionally substituted heterocyclic.

Embodiment 200. The compound or salt of Embodiment 37, wherein each R ¹ is independently selected from methyl, ethyl and optionally substituted diazaspiro[3.3]heptane.

Embodiment 201. A compound or salt of any one of Embodiments 1-19, [0449]-[0460], [0472]-[0482], [0495], [0497]-[0506] and 33-38, wherein ^Z1 and ^Z2 are independently selected from -C( ^R2 ) _2- , ^-NR3- , -O- and -S-.

Embodiment 202. The compound or salt of Embodiment 40, wherein Z ¹ and Z ² are independently -C(R ² ) ₂ -.

Embodiment 203. The compound or salt of Embodiment 40 or 41, wherein each of a and b is independently selected from 1 and 2.

Embodiment 204. A compound or salt according to any one of Embodiments 1-19, [0449]-[0460], [0472]-[0482], [0495], [0497]-[0506] and 33-42, wherein Y ¹ is selected from -C(R ² ) ₂ -, -NR ³ -, -O- and -S-.

Embodiment 205. The compound or salt of Embodiment 43, wherein Y ¹ is selected from -C(R ² ) ₂ - and -NR ³ .

Embodiment 206. The compound or salt of Embodiment 44, wherein Y ¹ is -C(R ² ) ₂ - and two R ² substituents are combined to form a ring selected from an optionally substituted heterocyclic ring and an optionally substituted carbocyclic ring.

Embodiment 207. The compound or salt of Embodiment 45, wherein Y ¹ is -C(R ² ) ₂ - and the two R ² substituents are combined to form a ring selected from the group consisting of an optionally substituted heterocyclic ring.

Embodiment 208. A compound or salt of any one of Embodiments 1-19, [0449]-[0460], [0472]-[0482], [0495], [0497]-[0506] and 33-43, wherein the compound or salt is represented by formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is selected from an optionally substituted azacyclobutane, an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted piperidine, an optionally substituted morpholine, an optionally substituted tetrahydrothienopyrrole dioxide and an optionally substituted dihydroindole.

Embodiment 209. The compound or salt of Embodiment 47, wherein the compound or salt is represented by formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring system is selected from .

Embodiment 210. A compound or salt according to any one of Embodiments 33-39, wherein the compound is selected from: .

Embodiment 211. A compound or salt according to any one of Embodiments 1-32, [0449]-[0470], [0472]-[0493], [0495]-[0516] or 33-109, wherein R ⁴ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle and optionally substituted 3 to 4 membered heterocycloalkyl.

Embodiment 212. The compound or salt of Embodiment 49, wherein R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl.

Embodiment 213. The compound or salt of Embodiment 50, wherein R ⁴ is selected from hydrogen, methyl and -CHF ₂ .

Embodiment 214. A compound or salt according to any one of Embodiments 1-32, [0449]-[0470], [0472]-[0493], [0495]-[0516] or 33-48, wherein R ⁴ is selected from hydrogen, halogen and -CN.

Embodiment 215. A compound or salt according to any one of Embodiments 1-32, [0449]-[0470], [0472]-[0493], [0495]-[0516] or 33-48, wherein R ⁴ is selected from hydrogen.

Embodiment 216. A compound or salt according to any one of Embodiments 1-32, [0449]-[0470], [0472]-[0493], [0495]-[0516] or 33-48, wherein R ⁴ is not optionally substituted phenyl.

Embodiment 217. A compound or salt according to any one of Embodiments 1-32, [0449]-[0470], [0472]-[0493], [0495]-[0516] or 33-48, wherein R ⁴ is not optionally substituted alkyl.

Embodiment 218. A compound or salt according to any one of Embodiments 1-32, [0449]-[0470], [0472]-[0493], [0495]-[0516], 33-39 or 49 to 117, wherein R ⁵ is selected from hydrogen, halogen, optionally substituted C _1-2 alkyl, optionally substituted C _3-4 carbocycle and optionally substituted 3 to 4 membered heterocycloalkyl.

Embodiment 219. The compound or salt of Embodiment 56, wherein R ⁵ is selected from hydrogen, halogen and optionally substituted C _1-2 alkyl.

Embodiment 220. The compound or salt of Embodiment 57, wherein R ⁵ is selected from hydrogen and fluorine.

Embodiment 221. A compound or salt according to any one of Embodiments 1-32, [0449]-[0470], [0472]-[0493], [0495]-[0516], 33-39 or 49-58, wherein ^R6 is selected from hydrogen, halogen, optionally substituted _C1-2 alkyl, optionally substituted _C3-4 carbocycle and optionally substituted 3-4 membered heterocycloalkyl.

Embodiment 222. The compound or salt of Embodiment 59, wherein R ⁶ is selected from hydrogen, halogen and optionally substituted C _1-2 alkyl.

Embodiment 223. The compound or salt of Embodiment 60, wherein R ⁶ is hydrogen.

Embodiment 224. A compound or salt according to any one of Embodiments 1-32, [0449]-[0470], [0472]-[0493], [0495]-[0516], 33-39 or 49-61, wherein R ⁷ is hydrogen.

Embodiment 225. A pharmaceutical composition comprising a compound or salt according to any one of Embodiments 1 to 62 and a pharmaceutically acceptable excipient.

Embodiment 226. A method for treating cancer, comprising administering the pharmaceutical composition of Embodiment 68 to a subject in need thereof.

Embodiment 227. The method of embodiment 69, wherein the cancer is a solid tumor.

Embodiment 228. The method of embodiment 69 or 70, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer and brain cancer.

Embodiment 229. The method of embodiment 71, wherein the cancer is ovarian cancer or breast cancer.

Embodiment 230. A method of inhibiting cyclin-dependent kinase (CDK) in a cell using a compound or salt of any one of Embodiments 1 to 62 or a pharmaceutical composition of Embodiment 68.

Embodiment 231. The method of embodiment 73, wherein the CDK is selected from CDK 2, CDK 4, CDK6 or any combination thereof.

Embodiment 232. The method of embodiment 74, wherein the CDK is selected from CDK 2/4, CDK 2/6, CDK 4/6 and CDK 2/4/6.

Embodiment 233. The method of embodiment 75, wherein the CDK is CDK 2/4/6.

Now that the present invention has been generally described, the present invention will be more readily understood with reference to the following examples, which are included only to illustrate certain aspects and embodiments of the present invention and are not intended to limit the present invention in any way.

The following synthetic schemes are provided for the purpose of illustration and not limitation. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that one skilled in the art will be able to prepare these compounds by analogous methods or by combining other methods known to one skilled in the art. It should also be understood that one skilled in the art will be able to prepare in a manner similar to that described below by using appropriate starting materials and modifying the synthetic pathways as necessary. In general, starting materials and reagents can be obtained from commercial suppliers or synthesized from sources known to one skilled in the art or prepared as described herein. General Synthetic Schemes 1-3 Scheme 1 Process 2 Process 3 Intermediate Intermediate 1 : 8 - Chloro -2-( methylthio ) pyrido [3,4-d] pyrimidine Step 1 : ( E )-5-(2- ethoxyvinyl )-2-( methylthio ) pyrimidine -4- carboxylic acid methyl ester

To a stirred mixture of methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (7.8 g, 29.64 mmol) and 2-[( E )-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.45 g, 44.46 mmol) in tetrahydrofuran (60 mL) under nitrogen atmosphere was added sodium carbonate (4.71 g, 44.46 mmol) in water (20 mL) and Pd(dppf) _Cl2 (1.08 g, 1.48 mmol). The resulting mixture was heated to 65 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a crude product. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether, 85:15) to give ( E )-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylic acid methyl ester (5.30 g, 70.3% yield). LCMS (ESI) m/z = 255 [M+H] ⁺ . Step 2 : ( E )-5-(2- ethoxyvinyl )-2-( methylthio ) pyrimidine -4- carboxamide

To a stirred mixture of methyl ( E )-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate (4.8 g, 18.87 mmol) in methanol (5 mL) was added a solution of ammonium in methanol (7 M, 50 mL, 350 mmol). The resulting mixture was heated to 85 °C and stirred in a sealed tube overnight. The resulting mixture was cooled to room temperature and concentrated under vacuum to give the crude title product (4.2 g). The crude product was used directly in the next step without further purification.

LCMS (ESI) m/z = 240 [M+H] ⁺ . Step 3 : 2-( Methylthio ) pyrido [3,4-d] pyrimidin -8( 7H ) -one

To a stirred mixture of ( E )-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxamide (4.2 g, 17.55 mmol) in toluene (50 mL) was added p-toluenesulfonic acid (0.30 g, 1.75 mmol). The resulting mixture was heated to 90 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum to give the crude product. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude title product (4.4 g). The crude product was used directly in the next step without further purification. LCMS (ESI) m/z = 194 [M+H] ⁺ . Step 4 : 8- Chloro -2-( methylthio ) pyrido [3,4-d] pyrimidine

A mixture of 2-(methylthio)pyrido[3,4-d]pyrimidin-8( 7H )-one (4.2 g, 21.73 mmol) in phosphorus oxychloride (150 mL) was heated to 80 °C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under high vacuum. The residue was carefully quenched by the addition of saturated aqueous sodium bicarbonate solution (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 2:1) to give 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (3.70 g, 92.4% yield). LCMS (ESI) m/z = 212 [M+H] ⁺ . Intermediate 2 : 6- Methyl -2-( methylthio ) pyrido [3,4-d] pyrimidin -8(7H)-one Reaction Scheme Detailed procedure Step 1 : 5- Bromo -2-( methylthio )-N- phenylpyrimidine -4- carboxamide

Oxalyl dichloride (13.25 g, 104.4 mmol) was added to a solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (20 g, 80.3 mmol) in DCM (800 mL) at 0°C. One drop of DMF was added and the resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in DCM (800 mL) and aniline (11.96 g, 128.5 mmol) and _Et3N (17.06 g, 168.6 mmol) were added at 0°C. The resulting mixture was stirred at room temperature for 24 h. The reaction was quenched by the addition of aqueous HCl (0.5 N, 500 mL) and extracted with DCM (2×500 mL). The combined organic layers were washed with water (2×500 mL) and brine (500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product 5-bromo-2-(methylthio)-N-phenylpyrimidine-4-carboxamide (26 g crude material). The crude product was used as is in the next step. LCMS (ESI-MS) m/z = 324.0, 326.0 [M+H] ⁺ . Step 2 : 6- Methyl -2-( methylthio ) pyrido [3,4-d] pyrimidin -8(7H) -one

To a solution of 5-bromo-2-(methylthio)-N-phenylpyrimidine-4-carboxamide (26 g, 80.2 mmol) in ACN (270 mL) was added pentane-2,4-dione (16.06 g, 160.4 mmol), CuI (1.53 g, 8.02 mmol) and Cs ₂ CO ₃ (52.26 g, 160.4 mmol). The resulting mixture was heated to 85 °C and stirred overnight. Ammonium acetate (101.8 g, 1.72 mol) and acetic acid (200 mL) were added, and the resulting mixture was heated to 85 °C and stirred for 5 h. After cooling to room temperature, the reaction mixture was concentrated under high vacuum until most of the liquid evaporated. The residue was then neutralized by adding saturated aqueous NaOH (about 500 mL) at 0°C, followed by saturated aqueous NaHCO ₃ at 0°C until the pH was adjusted to 6-7. The aqueous layer was extracted with DCM (2×1 L). The combined organic layers were washed with brine (2×500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The residue was purified by flash column chromatography eluting with 20% to 80% ethyl acetate in petroleum ether followed by 0% to 10% MeOH in DCM to give the desired product 6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (5.8 g, 35% yield for 3 steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.9 (s, 1H), 9.07 (s, 1H), 6.31 (s, 1H), 2.58 (s, 3H), 2.22 (s, 3H). LCMS (ESI-MS) m/z = 208.0 [M+H] ⁺ . Intermediate 3 : 8- Chloro -6- methyl -2-( methylthio ) pyrido [3,4-d] pyrimidine 8- Chloro -6- methyl -2-( methylthio ) pyrido [3,4-d] pyrimidine

To a solution of 6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (4 g, 19.30 mmol) in toluene (20 mL) was added POCl ₃ (32.00 mL). The mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure, quenched with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using ethyl acetate/petroleum ether (0-20%) to give 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (2.01 g, 46.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.47 (s, 1H), 7.79 (d, J = 0.6 Hz, 1H), 2.66 (s, 3H), 2.60 (s, 3H). LCMS (ESI-MS) m/z = 226.0 [M+H] ⁺ . Intermediate 4 : 8- chloro -6- methyl -2-( methylsulfonyl ) pyrido [3,4-d] pyrimidine and 8- chloro -6- methyl -2-( methylsulfinyl ) pyrido [3,4-d] pyrimidine

3-Chloroperoxybenzoic acid (6.88 g, 39.87 mmol) was added to 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (3.0 g, 13.29 mmol) in dichloromethane (50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, warmed to room temperature and stirred for 2 h. The reactant was quenched with saturated aqueous sodium bicarbonate solution (200 mL). The resulting mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA in PE, 0% to 100%) to give crude 8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine and 8-chloro-6-methyl-2-(methylsulfinyl)pyrido[3,4-d]pyrimidine (1.07 g, 30.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.99 (s, 1H), 8.09-8.06 (m, 1H), 3.54 (s, 3H), 2.81-2.66 (m, 3H). LCMS (ESI-MS) m/z = 257.9 [M+H] ⁺ . Intermediate 5 : 8- Bromo -6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine Reaction Scheme Detailed procedure Step 1 : 8- Bromo -6- methyl -2-( methylthio ) pyrido [3,4-d] pyrimidine

POBr3 (50 mL, 174.4 mmol) was added to 6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (5 g, 24.12 mmol) in MeCN (50 mL). The mixture was stirred at 70 °C for 3 h and concentrated under reduced pressure. The residue was quenched with aqueous sodium bicarbonate at 0 °C and extracted with EA (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using EA/PE (0-20%) to give 8-bromo-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (2.2 g, 33.8% yield). LCMS (ESI-MS) m/z = 270.0, 272.0 [M+H] ⁺ . Step 2 : 8- bromo -6- methyl -2-( methylsulfonyl ) pyrido [3,4-d] pyrimidine

3-Chloroperoxybenzoic acid (2.81 g, 16.28 mmol) was added to 8-bromo-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (2.2 g, 8.14 mmol) in DCM (50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then warmed to room temperature and stirred for 2 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution (200 mL). The resulting mixture was extracted with DCM (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA in PE, 0% to 100%) to give crude 8-bromo-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (1.3 g, 52.8% yield). LCMS (ESI-MS) m/z = 302.0, 304.0 [M+H] ⁺ . Step 3 : 8- Bromo -6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine

To a solution of 8-bromo-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (1.3 g, 4.30 mmol) in DMSO (10 mL) was added 1-(methylsulfonyl)piperidin-4-amine (0.77 g, 4.30 mmol), K ₂ CO ₃ (1.19 g, 8.60 mmol) and CsF (1.31 g, 8.60 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (2×40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA/PE, 0-20%) to give 8-bromo-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (206.1 mg, 10.8% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.18 (s, 1H), 8.12-7.96 (m, 1H), 7.57-7.54 (m, 1H), 4.09-3.94 (m, 1H), 3.64-3.51 (m, 2H), 2.90 (s, 6H), 2.57-2.45 (m, 2H), 2.18-2.01 (m, 2H), 1.71-1.56 (m, 2H). LCMS (ESI-MS) m/z = 400.0, 402.0 [M+H] ⁺ . Intermediate 6 : 8- Chloro - 6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2 - amine

A mixture of 8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (1 g, 3.88 mmol), 1-(methylsulfonyl)piperidin-4-amine (0.8 g, 4.26 mmol), DIEA (1.50 g, 11.64 mmol) and CsF (1.77 g, 11.64 mmol) in DMSO (5 mL) was stirred at 80 °C for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with CH ₂ Cl ₂ (3×100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 1:1) to give 8-chloro-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (505.8 mg, 33.3% yield). LCMS (ESI-MS) m/z = 356.0 [M+H] ⁺ . Intermediate 7 : 8- chloro - 6- cyclopropyl -2- methylsulfonylpyrido [3,4- d ] pyrimidine Step 1 : 5- Bromo -2-( methylthio ) -N - phenylpyrimidine -4- carboxamide

A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (15.0 g, 60.222 mmol) in anhydrous dichloromethane (225.0 ml) was cooled to 0°C. Oxalyl chloride (6.624 ml, 78.288 mmol) and one drop of anhydrous dimethylformamide were added under an argon atmosphere, and the reaction mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was concentrated under reduced pressure and the residue was redissolved in anhydrous dichloromethane (225.0 ml) and cooled to 0°C. Aniline (9.329 ml, 102.377 mmol) and triethylamine (18.467 ml, 132.488 mmol) were slowly added and the reaction mixture was stirred at room temperature for an additional 18 h. The reaction mixture was quenched with 0.5 M aqueous HCl and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 200 ml) and the combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by automated silica gel flash column chromatography (hexane to hexane/EtOAc 4:1) to give the title compound (17.34 g, 89% yield). ¹ H NMR (300 MHz, CHLOROFORM-d) δ 9.63 (bs, 1H), 8.86 (s, 1H), 7.77 - 7.71 (m, 2H), 7.42 (t, J = 7.9 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 2.66 (s, 3H). UPLC (ESI) [M+H] ⁺ = 323.70 and 325.70 (Br isotope pattern). Step 2 : 6- Cyclopropyl -2-( methylthio ) -7H , 8H - pyrido [3,4- d ] pyrimidin -8- one

A solution of 5-bromo-2-(methylthio) -N -phenylpyrimidine-4-carboxamide (10.0 g, 30.845 mmol), 1,3-dicyclopropylpropane-1,3-dione (7.633 ml, 61.69 mmol), cesium carbonate (20.1 g, 61.69 mmol) and copper (I) iodide (0.587 g, 3.085 mmol) in anhydrous acetonitrile (88.13 ml) was stirred at 85 ° C for 18 hours. Then, acetic acid (88.13 ml) and ammonium acetate (35.665 g, 462.677 mmol) were added, and the reaction mixture was stirred at 85 ° C for an additional 18 hours. The reaction mixture was concentrated under reduced pressure to remove acetonitrile, and the acetic acid-containing mixture was diluted with water (100 ml) and extracted with dichloromethane (3×100 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by automatic silica gel flash column chromatography (hexane/EtOAc 3:2 to EtOAc) to give the title compound (4.76 g, 66% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.01 (bs, 1H), 9.06 (s, 1H), 6.21 (s, 1H), 2.58 (s, 3H), 1.88 (tt, J = 8.3, 5.1 Hz, 1H), 1.04 - 0.92 (m, 2H), 0.89 - 0.77 (m, 2H). UPLC (ESI) [M+H] ⁺ = 233.90. Step 3 : 8- Chloro -6- cyclopropyl -2-( methylthio ) pyrido [3,4- d ] pyrimidine

A solution of 6-cyclopropyl-2-(methylthio) -7H , 8H -pyrido[3,4- d ]pyrimidin-8-one (4.76 g, 20.404 mmol) in phosphorus oxychloride (32.428 ml, 346.864 mmol) was stirred at 80 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was redissolved in ethyl acetate (50 ml) and quenched with saturated aqueous _NaHCO3 . The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over anhydrous _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by automated silica gel flash column chromatography (hexane to hexane/EtOAc 7:3) to give the title compound (4.58 g, 89% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 7.87 (s, 1H), 2.66 (s, 3H), 2.38 - 2.19 (m, 1H), 1.14 - 1.02 (m, 2H), 0.97 (ddd, J = 7.2, 5.1, 2.9 Hz, 2H). UPLC (ESI) [M+H] ⁺ = 251.85. Step 4 : 8- Chloro - 6-cyclopropyl -2- methylsulfonylpyrido [3,4- d ] pyrimidine

To a solution of 8-chloro-6-cyclopropyl-2-(methylthio)pyrido[3,4- d ]pyrimidine (2.5 g, 9.931 mmol) in dichloromethane (125.0 ml), 3-chloroperbenzoic acid (8.569 g, 49.656 mmol) was added portionwise, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture _was quenched by slow addition of 10% _{aqueous Na2S2O3} solution (50 ml) and extracted with dichloromethane (3×70 ml). The combined organic layers were washed with saturated aqueous _NaHCO3 solution, dried over anhydrous _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by automated silica gel flash column chromatography (hexane/EtOAc 4:1 to hexane/EtOAc 2:3) to afford the title compound (2.54 g, 89% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 8.12 (s, 1H), 3.52 (s, 3H), 2.42 (dq, J = 8.4, 4.7, 4.1 Hz, 1H), 1.17 (dt, J = 7.9, 3.0 Hz, 2H), 1.09 - 1.02 (m, 2H). UPLC (ESI) [M+H] ⁺ = 283.80. Intermediate 8 : 8- chloro -6- cyclopropyl - N- (1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4- d ] pyrimidin -2- amine

To a solution of 8-chloro-6-cyclopropyl-2-(methylsulfonyl)pyrido[3,4 -d ]pyrimidine (100 mg, 352 μmol) in anhydrous dimethylsulfoxide (1.8 mL) was charged 1-(methylsulfonyl)piperidin-4-amine (69.1 mg, 388 μmol), cesium fluoride (161 mg, 1.06 mmol) and N -ethyl- N -isopropylpropan-2-amine (137 mg, 184 μL, 1.06 mmol). The reaction vial was capped and stirred at 30 °C for 72 h. Afterwards, the crude mixture was diluted with water (50.0 mL) and extracted with dichloromethane (3 x 20.0 mL). The combined organic fractions were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo. The crude material was purified by flash chromatography on silica gel (heptane/EtOAc 1:1) to give the title compound (62.0 mg, 46% yield). LCMS (ESI) [M+H] ⁺ = 382.10 Intermediate 9 : 8- Chloro -6-( difluoromethyl )-2-( methylthio ) pyrido [3,4- d ] pyrimidine Reaction Scheme Detailed Procedure Step 1 : 5- Bromo -2-( methylthio ) pyrimidine -4- carboxylic acid methyl ester

To a solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (15.0 g, 60.222 mmol) in methanol (600.0 ml), sulfuric acid (98%, 3.852 ml, 72.266 mmol) was slowly added. The reaction mixture was stirred at 65 °C for 16 hours. Then, the reaction mixture was poured onto ice water and extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with saturated aqueous NaHCO ₃ solution, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to provide the title compound (15.02 g, 95% yield). The crude material was used in the next step without further purification. ¹ H NMR (300 MHz, chloroform-d) δ 8.73 (s, 1H), 4.02 (s, 3H), 2.59 (s, 3H). UPLC (ESI) [M+H] ⁺ = 262.70 and 264.65 (Br isotope pattern). Step 2 : 5-(3- methoxyprop -1- yn -1- yl )-2-( methylthio ) pyrimidine -4- carboxylic acid methyl ester

A solution of bis(benzonitrile)palladium chloride (0.729 g, 1.9 mmol), copper(I) iodide (0.362 g, 1.9 mmol) and tri-tert-butylphosphonium tetrafluoroborate (1.103 g, 3.801 mmol) in anhydrous dioxane (50.0 ml) was purged with hydrogen for 10 minutes. Then, N , N -diisopropylethylamine (23.171 ml, 133.024 mmol) was added and the mixture was stirred at room temperature for 5 min. Next, methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (5.0 g, 19.003 mmol) and 3-methoxyprop-1-yne (4.814 ml, 57.01 mmol) were slowly added, and the reaction mixture was stirred at 40°C overnight. The reaction mixture was cooled to room temperature, filtered through a celite pad and washed with ethyl acetate (50 mL) and dichloromethane (50 mL). The filtrate was concentrated under reduced pressure and purified with automated silica gel flash column chromatography (hexane to hexane/EtOAc 7:3) to provide the title compound (2.47 g, 52% yield). ¹ H NMR (300 MHz, chloroform-d) δ 8.73 (s, 1H), 4.39 (s, 2H), 4.01 (s, 3H), 3.50 (s, 3H), 2.63 (s, 3H). UPLC (ESI) [M+H] ⁺ = 252.80. Step 3 : 5-(3- methoxyprop-1-yn-1- yl ) -2- ( methylthio ) pyrimidine - 4- carboxamide

A solution of methyl 5-(3-methoxyprop-1-yn-1-yl)-2-(methylthio)pyrimidine-4-carboxylate (2.47 g, 9.79 mmol) in ammonia (7.0 N in methanol, 34.965 ml, 244.758 mmol) was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to provide the crude title compound (2.28 g, 98% yield). The crude product was used in the next step without further purification. ¹ H NMR (300 MHz, CHLOROFORM-d) δ 8.78 (s, 1H), 7.55 (s, 1H), 5.58 (s, 1H), 4.44 (s, 2H), 3.53 (s, 3H), 2.63 (s, 3H). UPLC (ESI) [M+H] ⁺ = 237.85. Step 4 : 6-( Methoxymethyl )-2-( methylthio ) -8H - pyrano [3,4- d ] pyrimidin -8- one

To a solution of 5-(3-methoxyprop-1-yn-1-yl)-2-(methylthio)pyrimidine-4-carboxamide (1.580 g, 6.660 mmol) in toluene (28.56 ml) was added p-toluenesulfonic acid monohydrate (0.916 g, 4.815 mmol). The reaction mixture was stirred at 110 °C for 48 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel flash column chromatography (hexane/EtOAc 7:3 to hexane/EtOAc 3:7) to provide the title compound (0.685 g, 43% yield). ¹ H NMR (300 MHz, chloroform-d) δ 8.85 (s, 1H), 6.53 (t, J = 1.2 Hz, 1H), 4.31 (d, J = 1.2 Hz, 2H), 3.53 (s, 3H), 2.70 (s, 3H). Step 5 : 6-( Hydroxymethyl )-2-( methylthio ) -8H - pyrano [3,4- d ] pyrimidin -8- one

A solution of 6-(methoxymethyl)-2-(methylthio) -8H -pyrano[3,4- d ]pyrimidin-8-one (1.275 g, 5.373 mmol) in anhydrous dichloromethane (44.78 ml) was cooled to -78 °C. Boron tribromide (1.0 M solution in dichloromethane, 32.247 ml, 32.247 mmol) was then added dropwise via an addition funnel, and the reaction mixture was stirred at the same temperature for 20 minutes. Next, the reaction mixture was warmed to -20 °C and stirred for another 2 hours and 30 minutes. The reaction mixture was quenched by dropwise addition of methanol followed by dropwise addition of saturated aqueous NaHCO ₃ solution (until gas evolution ceased). The mixture was extracted with dichloromethane (50 mL×3). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, concentrated under reduced pressure and purified by silica gel flash column chromatography (hexane/EtOAc 7:3 to hexane/EtOAc 1:9) to provide the title compound (0.787 g, 59% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.19 (s, 1H), 6.74 (d, J = 1.2 Hz, 1H), 5.74 (t, J = 6.0 Hz, 1H), 4.30 (dd, J = 6.0, 1.2 Hz, 2H), 2.61 (s, 3H) . Step 6 : 2-( Methylthio )-8 - oxo - 8H - pyrano [3,4- d ] pyrimidine -6- carbaldehyde

A solution of 6-(hydroxymethyl)-2-(methylthio) -8H -pyrano[3,4 -d ]pyrimidin-8-one (0.787 g, 3.173 mmol) in anhydrous dichloromethane (15.74 ml) was cooled to 0°C. Then, Dess-Martin periodinane (2.692 g, 6.347 mmol) was added portionwise. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The solid was filtered off, and the filtrate was washed with 0.5 M aqueous NaOH solution, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (hexane/EtOAc 8:2 to hexane/EtOAc 4:6) to provide the title compound (0.738 g, 100% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 9.35 (s, 1H), 7.78 (s, 1H), 2.65 (s, 3H) . Step 7 : 6-( Difluoromethyl )-2-( methylthio ) -8H - pyrano [3,4- d ] pyrimidin -8- one

A solution of 2-(methylthio)-8-oxo- 8H -pyrano[3,4- d ]pyrimidine-6-carbaldehyde (0.738 g, 3.167 mmol) in dichloromethane (22.13 ml) was cooled to 0 °C. Then, DAST (0.418 ml, 3.167 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for ₁ hour. The reaction mixture was quenched by the dropwise addition of 10% _{Na2S2O3 aqueous} solution (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (15 mL×3). The combined organic layers were dried over anhydrous _MgSO4 , filtered and concentrated under reduced pressure to provide the title compound (0.784 g, 92% yield). The crude material was used in the next step without further purification. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.24 (s, 1H), 7.25 (d, J = 1.6 Hz, 1H), 6.94 (t, J = 52.7 Hz, 1H), 2.63 (s, 3H). UPLC (ESI) [M+H] ⁺ = 244.85 . Step 8 : 6-( Difluoromethyl )-2-( methylthio ) -7H , 8H - pyrido [3,4- d ] pyrimidin -8- one

A solution of 6-(difluoromethyl)-2-(methylthio) -8H -pyrano[3,4 -d ]pyrimidin-8-one (0.734 g, 2.703 mmol) in ammonia (7.0 N in methanol, 21.242 ml, 148.691 mmol) was stirred at 80 °C for 16 h. The volatiles were removed under reduced pressure to provide the crude title compound (0.704 g, 96% yield) as a dark solid. The crude product was used in the next step without further purification. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 6.95 (d, J = 1.6 Hz, 1H), 6.88 (t, J = 53.8 Hz, 1H), 2.62 (s, 3H). UPLC (ESI) [M+H] ⁺ = 243.75 . Step 9 : 8- Chloro -6-( difluoromethyl )-2-( methylthio ) pyrido [3,4- d ] pyrimidine

A solution of 6-(difluoromethyl)-2-(methylthio) -7H , 8H -pyrido[3,4- d ]pyrimidin-8-one (0.704 g, 2.605 mmol) in phosphorus oxychloride (7.306 ml, 78.148 mmol) was stirred at 70°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in ethyl acetate (15 mL) and washed with saturated aqueous _NaHCO3 solution (15 mL). The aqueous layer was extracted with ethyl acetate (15 mL×3) and the combined organic layers were dried over anhydrous _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (hexane to hexane/EtOAc 7:3) to provide the title compound (0.277 g, 41% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 8.37 (s, 1H), 7.17 (t, J = 54.5 Hz, 1H), 2.71 (s, 3H). UPLC (ESI) [M+H] ⁺ = 261.80. Intermediate 10 : N- (5-(6- ethyl -2,6 -diazaspiro [3.3] hept -2- yl ) pyridin -2- yl ) formamide Reaction Scheme Detailed procedure Step 1 : 6-(6- nitropyridin -3- yl )-2,6 -diazaspiro [3.3] heptane -2- carboxylic acid tributyl ester

To a stirred mixture of tributyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (5 g, 25.21 mmol) and 5-fluoro-2-nitropyridine (5.37 g, 37.82 mmol) in dimethylsulfoxide (30 mL) was added N , N -diisopropylethylamine (9.78 g, 75.65 mmol). The resulting mixture was heated to 80 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the crude product. The residue was purified by trituration with petroleum ether/ethyl acetate (5:1, 100 mL) to give tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (6.78 g, 83.7% yield).

LCMS (ESI) m/z = 321 [M+H] ⁺ . Step 2 : 2-(6- nitropyridin -3- yl )-2,6 -diazaspiro [3.3] heptane

To a stirred mixture of tributyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (6.78 g, 21.16 mmol) in dichloromethane (80 mL) was added trifluoroacetic acid (16 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The residue was diluted with dichloromethane (100 mL) and concentrated again under vacuum to give crude 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (6 g). The crude product was used directly in the next step without further purification. LCMS (ESI) m/z = 221 [M+H] ⁺ . Step 3 : 2- ethyl -6-(6- nitropyridin -3- yl )-2,6 -diazaspiro [3.3] heptane

A solution of 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (6 g, 18.9 mmol) in methanol (100 mL) was treated with triethylamine (5.73 g, 56.7 mmol) for 10 min followed by the addition of acetaldehyde (4.16 g, 94.5 mmol), acetic acid (0.23 mL, 4.08 mmol) and sodium cyanoborohydride (2.51 g, 39.8 mmol). The resulting mixture was stirred at room temperature for 3 h and concentrated under vacuum. The residue was diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by wet trituration with dichloromethane (100 mL) to give 2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (4 g, 58.9% yield) as an orange solid. LCMS (ESI) m/z = 249 [M+H] ⁺ . Step 4 : 5-(6- ethyl -2,6 -diazaspiro [3.3] hept -2- yl ) pyridin -2- amine

A solution of 2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (4 g, 16.11 mmol), ammonium chloride (4.31 g, 80.55 mmol), iron powder (9.00 g, 161.100 mmol) and water (20 mL) in ethanol (60 mL) was stirred at 80 °C for 1 hour. The resulting mixture was filtered and the filter cake was washed with ethanol (100 mL). The filtrate was concentrated under vacuum to give the crude product. The residue was purified by reverse phase flash chromatography (C18 silica gel, acetonitrile/water (with 10 mmol/L NH ₄ HCO ₃ ) gradient) to give 5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-amine (2 g, 56.6% yield). LCMS (ESI) m/z = 219 [M+H] ⁺ . Step 5 : N- (5-(6- ethyl -2,6 -diazaspiro [3.3] hept -2- yl ) pyridin -2- yl ) formamide

A solution of acetic anhydride (2 mL) in formic acid (4 mL) was stirred at room temperature for 1 hour, followed by the addition of 5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-amine (400 mg, 1.83 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution (200 mL) to pH = 7 and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, and the residue was purified by preparative reverse phase HPLC (acetonitrile/water (with 10 mM NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ ) gradient) to give the title compound (70 mg , 15.3% yield). LCMS (ESI ) m/z = 247 [M+H] ⁺ . Intermediate 12 : 1-( cyclopropylsulfonyl ) piperidin -4- amine Reaction Scheme Detailed procedure Step 1 : (1-( cyclopropylsulfonyl ) piperidin -4- yl ) carbamic acid tert-butyl ester

To a solution of cyclopropanesulfonyl chloride (7.02 g, 49.93 mmol) and DIEA (19.36 g, 149.79 mmol) in DCM (100 mL) at 0 °C, tributyl N-(piperidin-4-yl)carbamate (10 g, 49.93 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (500 mL). The aqueous solution was extracted with CH ₂ Cl ₂ (3×500 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by wet trituration with EA (100 mL) to give tributyl (1-(cyclopropylsulfonyl)piperidin-4-yl)carbamate (10 g, 59.2% yield). LCMS (ESI-MS) m/z = 249.1 [M+H-56] ⁺ . Step 2 : 1-( cyclopropylsulfonyl ) piperidin -4- amine

A solution of tributyl (1-(cyclopropylsulfonyl)piperidin-4-yl)carbamate (10 g, 32.87 mmol) in TFA (15 mL) and DCM (45 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give 1-(cyclopropylsulfonyl)piperidin-4-amine (8 g). LCMS (ESI-MS) m/z = 205.1 [M+H] ⁺ . Intermediate 13 : 8- Chloro -N-(1-( cyclopropylsulfonyl ) piperidin -4- yl )-6- methylpyrido [ 3,4-d] pyrimidin -2- amine

A solution of 8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (1 g, 3.88 mmol), 1-(cyclopropanesulfonyl)piperidin-4-amine (1.59 g, 7.76 mmol), DIEA (1.50 g, 11.64 mmol) and CsF (1.77 g, 11.64 mmol) in DMSO (10 mL) was stirred at 80 °C for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (3×200 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 1:1) to give 8-chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine (505.8 mg, 33.3% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.08 (d, J = 7.4 Hz, 1H), 7.56 (s, 1H), 4.03 (s, 1H), 3.69-3.57 (m, 2H), 3.09-2.92 (m, 2H), 2.69-2.55 (m, 1H), 2.17-1.89 (m, 2H), 1.71-1.55 (m, 2H), 1.42-1.30 (m, 1H), 1.29-1.13 (m, 2H), 1.05-0.97 (m, 2H), 0.97-0.91 (m, 2H). LCMS (ESI-MS) m/z = 382.2 [M+H] ⁺ . Intermediate 14 : 1-((1- methyl - 1H- pyrazol -4- yl ) sulfonyl ) piperidin -4- amine Reaction Scheme Step 1 : (1-((1- methyl -1H- pyrazol -4- yl ) sulfonyl ) piperidin -4- yl ) carbamic acid tert-butyl ester

To a stirred mixture of 1-methyl-1H-pyrazole-4-sulfonyl chloride (7 g, 38.75 mmol) and DIEA (15.03 g, 116.27 mmol) in DCM (70 mL) at 0 °C, tributyl piperidin-4-ylcarbamate (7.76 g, 38.75 mmol) was added dropwise. The resulting mixture was stirred at 0 °C for 1 h. The resulting mixture was diluted with water (500 mL). The aqueous solution was extracted with CH ₂ Cl ₂ (3×500 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica _gel column chromatography ( _CH2Cl2 /MeOH, 99:1) to give tributyl (1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate (9 g, 64.1% yield). LCMS (ESI-MS) m/z = 289.2 [M+H-56] ⁺ . Step 2 : 1-((1- methyl -1H- pyrazol -4- yl ) sulfonyl ) piperidin -4- amine

A solution of tributyl (1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate (6 g, 17.42 mmol) in TFA (12 mL) and DCM (36 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give 1-(1-methylpyrazol-4-ylsulfonyl)piperidin-4-amine (6.5 g crude material). LCMS (ESI-MS) m/z = 245.2 [M+H] ⁺ . Intermediate 15 : 8- Chloro -6- methyl -N-(1-((1- methyl -1H- pyrazol -4- yl ) sulfonyl ) piperidin -4- yl ) pyrido [3,4- d ] pyrimidin -2- amine

A solution of 1-(1-methylpyrazol-4-ylsulfonyl)piperidin-4-amine (6.07 g, 24.83 mmol), 8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (4 g, 15.52 mmol), DIEA (6.02 g, 46.56 mmol) and CsF (7.07 g, 46.56 mmol) in DMSO (20 mL) was stirred at 80 °C for 1 h. The reaction mixture was diluted with water (500 mL) and then extracted with EA (3×500 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE/EA, 1:4) to give 8-chloro-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (2.5 g, 37.4% yield). LCMS (ESI-MS) m/z = 422.0 [M+H] ⁺ . Intermediate 16 : 8- chloro -N-(6- fluoro -2-( methylsulfonyl ) isoindolin -5- yl )-6- methylpyrido [ 3,4-d] pyrimidin -2- amine Reaction Scheme Detailed procedure Step 1 : 5- Fluoroisoindoline -1,3- dione

To a solution of 5-fluoro-2-benzofuran-1,3-dione (10 g, 60.20 mmol) in toluene ( ₃₀ mL) at 110 °C, urea (4.34 g, 72.24 mmol) was added portionwise. The resulting mixture was stirred at 110 °C for 18 h. The mixture was allowed to cool to room temperature. The residue was purified by wet trituration with H20 (100 mL). This produced 5-fluoroisoindoline-1,3-dione (9 g, 38.9% yield). LCMS (ESI-MS) m/z = 166.0 [M+H] ⁺ . Step 2 : 5- Fluoro -6- nitroisoindoline -1,3- dione

To a solution of 5-fluoroisoindoline-1,3-dione (9 g, 54.50 mmol) in H ₂ SO ₄ (90 mL) at 0° C., HNO ₃ (9 mL) was added portionwise. The resulting mixture was stirred at 80° C. for another 30 min. The mixture was cooled to 0° C. The reactants were quenched with cold water at 0° C. The resulting mixture was stirred at 0° C. for another 30 min. The precipitated solid was collected by filtration and washed with H ₂ O (3×500 mL) to give the desired product 5-fluoro-6-nitroisoindoline-1,3-dione (4 g, 34.9% yield). LCMS (ESI-MS) m/z = 211.0 [M+H] ⁺ . Step 3 : 5- Fluoro -6- nitroisoindoline

To a solution of 5-fluoro-6-nitroisoindoline-1,3-dione (5 g, 23.79 mmol) in THF (217.5 mL) at -10 °C, _NaBH4 (0.87 g, 22.99 mmol) and BF3-Et2O (35.56 g, 250.57 mmol) were added portionwise. The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 18 h and concentrated under vacuum to give crude 5-fluoro-6-nitroisoindoline (1.5 g crude material). LCMS (ESI-MS) m/z = 183.0 [M+H] ⁺ . Step 4 : 5- Fluoro -2-( methylsulfonyl )-6- nitroisoindoline

To a solution of 5-fluoro-6-nitroisoindoline (1.5 g, 8.23 mmol) in DCM (10 mL) was added Et ₃ N (4.50 mL, 32.36 mmol) at 0°C under nitrogen atmosphere over 3 min. MsCl (1.71 g, 14.90 mmol) was then added portionwise at 0°C. The resulting mixture was stirred at room temperature overnight. The aqueous layer was extracted with EtOAc (2×200 mL). The resulting mixture was washed with saturated aqueous sodium chloride solution (2×200 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA and _CH2Cl2 /MeOH (5:1) to give 5-fluoro- _2- (methylsulfonyl)-6-nitroisoindolin (500 mg, 23.3% yield). LCMS (ESI-MS) m/z = 261.0 [M+H] ⁺ . Step 5 : 6- Fluoro -2-( methylsulfonyl ) isoindolin -5- amine

To a solution of 5-fluoro-2-(methylsulfonyl)-6-nitroisoindoline (500 mg, 1.92 mmol) in EtOH (12 mL) and H ₂ O (4 mL) at 80° C., Fe (1.07 g, 19.21 mmol) and NH ₄ Cl (411.08 mg, 7.68 mmol) were added portionwise. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 h and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE/EA (1:1) to give 6-fluoro-2-(methylsulfonyl)isoindoline-5-amine (280 mg, 63.3% yield). LCMS (ESI-MS) m/z = 231.0 [M+H] ⁺ . Step 6 : N-(6- fluoro -2-( methylsulfonyl ) isoindolin -5- yl ) formamide

To a solution of 6-fluoro-2-(methylsulfonyl)isoindolin-5-amine (110 mg, 0.47 mmol) in THF (2 mL) was added 1,2,3-benzotriazole-1-carbaldehyde (70.29 mg, 0.47 mmol). The resulting mixture was stirred at 65 °C overnight under a nitrogen atmosphere and allowed to cool to room temperature. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE/EA (1:1) to give N-(6-fluoro-2-(methylsulfonyl)isoindolin-5-yl)formamide (60 mg, 48.6% yield). LCMS (ESI-MS) m/z = 259.0 [M+H] ⁺ . Step 7 : 8- Chloro -N-(6- fluoro -2-( methylsulfonyl ) isoindolin -5- yl )-6 -methylpyrido [3,4-d] pyrimidin -2- amine

To a solution of N-(6-fluoro-2-(methylsulfonyl)isoindolin-5-yl)formamide (55 mg, 0.21 mmol) in dimethylformamide (2 mL) was added sodium hydroxide (25.55 mg, 1.06 mmol, 60% in mineral oil). The resulting mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. 8-Chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (54.88 mg, 0.21 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous NH ₄ Cl solution (60 mL) at room temperature, diluted with EtOAc (500 mL) and washed with saturated aqueous sodium chloride solution (3×500 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to give 8-chloro-N-(6-fluoro-2-(methylsulfonyl)isoindoline-5-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine (60 mg, 69.1% yield). LCMS (ESI-MS) m/z = 408.1 [M+H] ⁺ . Intermediate 17 : 1-(2- methyl -2- azaspiro [3.3] hept -6- yl )-1H- pyrazol - 4- amine Reaction Scheme Detailed procedure Step 1 : 6-(4- nitro -1H- pyrazol -1- yl )-2- azaspiro [3.3] heptane -2- carboxylic acid tributyl ester

To a solution of tributyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (10 g, 46.88 mmol) in THF (100 mL) was added 4-nitropyrazole (5.30 g, 46.88 mmol), DIAD (9.48 g, 46.88 mmol) and PPh ₃ (12.30 g, 46.88 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum and purified by silica gel column eluting with DCM/MeOH=10:1 to give the title product (8 g, 49.8% yield). LCMS (ESI-MS) m/z =309.1 [M+H] ⁺ . Step 2 : 6-(4- nitro -1H- pyrazol -1- yl )-2- azaspiro [3.3] heptane

A mixture of tributyl 6-(4-nitropyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (8 g, 25.94 mmol), TFA (3 mL) and DCM (6 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum to give 6-(4-nitro-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (5 g, 83.3% yield). LCMS (ESI-MS) m/z = 209.1 [M+H] ⁺ . Step 3 : 2- Methyl -6-(4- nitro -1H- pyrazol -1- yl )-2- azaspiro [3.3] heptane

A mixture of 6-(4-nitropyrazol-1-yl)-2-azaspiro[3.3]heptane (4.5 g, 21.61 mmol) and HCHO (1.95 g, 64.83 mmol) in MeOH (50 mL) was stirred at room temperature for 2 h. NaBH ₃ CN (2.72 g, 43.22 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. The mixture was purified by silica gel column chromatography eluting with DCM/MeOH = 10:1 to give 2-methyl-6-(4-nitro-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (3.5 g, 58.3% yield). LCMS (ESI-MS) m/z = 223.1 [M+H] ⁺ . Step 4 : 1-(2- methyl -2- azaspiro [3.3] hept -6- yl )-1H- pyrazol - 4 - amine

Pd/C (350 mg, 10%/carbon) was added to a solution of 2-methyl-6-(4-nitropyrazol-1-yl)-2-azaspiro[3.3]heptane (3.5 g, 15.74 mmol) in MeOH (50 mL) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 1-(2-methyl-2-azaspiro[3.3]hept - 6 -yl)-1H-pyrazol-4-amine ( 3 g, 99.1% yield). LCMS (ESI-MS) m/z = 193.1 [M+H] ⁺ . Intermediate 18 : 2-( Methylsulfonyl ) isoindolin - 5- amine Reaction Scheme Detailed procedure Step 1 : 2-( Methylsulfonyl )-5- nitroisoindole

Methanesulfonyl methanesulfonate (1326.39 mg, 7.61 mmol) was added to a stirred solution of 5-nitro-2,3-dihydro-1H-isoindole (500 mg, 3.04 mmol) and _Et3N (462.31 mg, 4.56 mmol) in DCM (10 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water ( ₁₀₀ mL) at 0°C. The mixture was extracted with _CH2Cl2 (3 x 150 mL). The combined organic layers were dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to obtain crude 2-(methylsulfonyl)-5-nitroisoindolin (500 mg, 67.7% yield). No mass signal. Step 2 : 2-( methylsulfonyl ) isoindolin -5- amine

Pd/C (219.6 mg, 2.06 mmol, 10%/carbon) was added to a solution of 2-(methylsulfonyl)-5-nitroisoindoline (500 mg, 2.06 mmol) in MeOH (10 mL) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The reaction mixture was filtered. The filter cake was washed with MeOH (4×100 mL) and the combined filtrate was concentrated under reduced pressure to give crude 2-(methylsulfonyl)isoindoline-5-amine (400 mg, 91.3% yield). LCMS (ESI-MS) m/z = 213.1 [M+H] ⁺ . Intermediate 19 : 2-(1-( methylsulfonyl ) azacyclobutane -3- yl )-5- nitroisoindoline Reaction Scheme Detailed procedure Step 1 : 3-(5- nitroisoindolin - 2 - yl ) azinecyclobutane - 1- carboxylic acid tert-butyl ester

A mixture of 5-nitro-2,3-dihydro-1H-isoindole hydrochloride (1.8 g, 8.97 mmol) and tributyl 3-oxazolidinone-1-carboxylate (1.54 g, 8.97 mmol) in MeOH (40 mL) was stirred at room temperature for 1 h. NaBH ₃ CN (1.13 g, 17.94 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and quenched with water (100 mL). The mixture was extracted with EA (3×100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using EA/PE (30%) to give tert-butyl 3-(5-nitroisoindolin-2-yl)azinecyclobutane-1-carboxylate (2.4 g, 80.8% yield). LCMS (ESI-MS) m/z = 320.2 [M+H] ⁺ . Step 2 : 2-( Azacyclobutane - 3- yl )-5 - nitroisoindolin

A mixture of tert-butyl 3-(5-nitroisoindolin-2-yl)azetidin-1-butanecarboxylate (2.4 g, 7.51 mmol) in TFA (4 mL) and DCM (12 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated and purified by silica gel column chromatography eluting with DCM (0.5% Et ₃ N) / MeOH (1:1) to give 2-(azetidin-3-yl)-5-nitroisoindolin (850 mg, 51.6% yield). LCMS (ESI-MS) m/z = 220.1 [M+H] ⁺ . Step 3 : 2-(1- ( methylsulfonyl ) azacyclobutane - 3 - yl ) -5 - nitroisoindole

Methanesulfonic anhydride (699.16 mg, 4.01 mmol) was added to a mixture of 2-(azacyclobutan-3-yl)-5-nitroisoindoline (800 mg, 3.64 mmol) and _Et3N (1107 mg, 10.94 mmol) in DCM (12 mL) cooled to 0°C. The reaction mixture was stirred at room temperature overnight and quenched with water (60 mL). The resulting mixture was extracted with DCM (3 x 60 mL). The combined organic layers were dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE/EA (61%) to give 2-(1-(methylsulfonyl)azacyclobutan-3-yl)-5-nitroisoindolin (850 mg, 66.6% yield). LCMS ( ESI - MS ) m/z = 298.1 [M+H] ⁺ . Step 4 : 2-(1-( methylsulfonyl ) azacyclobutan - 3- yl ) isoindolin - 5 - amine

Pd/C (143.17 mg, 1.34 mmol) was added to a mixture of 2-(1-(methylsulfonyl)azetidin-3-yl)-5-nitroisoindolin (800 mg, 2.69 mmol) in MeOH (15 mL) under nitrogen atmosphere, and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 1 h. The mixture was filtered and the filter cake was washed with MeOH (2×50 mL). The filtrate was concentrated under reduced pressure to give crude 2-(1-(methylsulfonyl)azetidin-3-yl)isoindolin-5-amine (600 mg, 65.3% yield). LCMS (ESI-MS) m/z = 268.1 [M+H] ⁺ . Intermediate 20 : 2-(3-(4- amino -1H- pyrazol -1- yl ) azinecyclobutan -1- yl ) acetonitrile Reaction Scheme Detailed procedure Step 1 : 3-(4- nitro -1H- pyrazol -1- yl ) azinecyclobutane -1- carboxylic acid tert-butyl ester

To a solution of tert-butyl 3-hydroxyazacyclobutane-1-carboxylate (3 g, 17.32 mmol) and 4-nitropyrazole (1.96 g, 17.32 mmol) in THF (20 mL), PPh ₃ (6.81 g, 25.98 mmol) was added portionwise at 0° C. and DIAD (5.25 g, 25.98 mmol) was added at room temperature. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography (PE/EA, 5:1) to give tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azacyclobutane-1-carboxylate (5 g). LCMS (ESI-MS) m/z = 269.1 [M+H] ⁺ . Step 2 : 1-( Azocyclobutane -3- yl )-4- nitro -1H- pyrazole

A mixture of tributyl 3-(4-nitro-1H-pyrazol-1-yl)azetidin-1-butane-1-carboxylate (6 g, 22.36 mmol) and TFA (20 mL) in DCM (60 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum to give crude 1-(azetidin-3-yl)-4-nitro-1H-pyrazole (4 g). LCMS (ESI-MS) m/z = 169.1 [M+H] ⁺ . Step 3 : 2-(3-(4- nitro -1H- pyrazol -1- yl ) azetidin -1- yl ) acetonitrile

To a solution of 1-(azacyclobutan-3-yl)-4-nitro-1H-pyrazole (1.5 g, 8.92 mmol) in MeCN (50 mL) was added 2-bromoacetonitrile (1.60 g, 13.38 mmol) and N,N-diisopropylethylamine (3.46 g, 26.76 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA, 1:1) to give the desired product 2-(3-(4-nitro-1H-pyrazol-1-yl)azacyclobutan-1-yl)acetonitrile (300 mg, 16.23%). LCMS (ESI-MS) m/z = 208.1[M+H] ⁺ . Step 4 : 2-(3-(4- amino -1H- pyrazol -1- yl ) azinecyclobutane -1- yl ) acetonitrile

To a solution of 2-(3-(4-nitro-1H-pyrazol-1-yl)azepanobutyl-1-yl)acetonitrile (200 mg, 0.96 mmol) and _NH4Cl (206.53 mg, 3.86 mmol) in water (3 mL) and EtOH (9 mL) at 80 °C was added Fe (539.06 mg, 9.65 mmol) portionwise. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. The reaction mixture was filtered and the filtrate was concentrated, diluted with water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were dried over _{anhydrous Na2SO4} , filtered and concentrated under vacuum to give crude 2-(3-(4-amino-1H-pyrazol-1-yl)azepanobutyl-1-yl)acetonitrile (120 mg, 70.2% yield). LCMS (ESI-MS) m/z = 178.1 [M+H] ⁺ . Intermediate 21 : 1-((1-( dimethylamino ) cyclopropyl ) methyl )-1H- pyrazol -4- amine Reaction Scheme Detailed procedure Step 1 : (1-( dimethylamino ) cyclopropyl ) methanol

NaBH ₃ CN (2.89 g, 45.9 mmol) was added to a solution of (1-aminocyclopropyl)methanol (2 g, 22.9 mmol) and paraformaldehyde (6.20 g, 68.8 mmol) in MeOH (20 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and purified by silica gel column chromatography eluting with MeOH in DCM (0% to 20%). The fractions with the desired mass signal were combined and concentrated under vacuum to give the desired product (1-(dimethylamino)cyclopropyl)methanol (600 mg, 22.7% yield). LCMS (ESI-MS) m/z =116.1 [M+H] ⁺ . Step 2 : N,N- dimethyl -1-((4- nitro -1H- pyrazol -1- yl ) methyl ) cyclopropane -1- amine

DIAD (1.4 g, 7.16 mmol) was added to a solution of (1-(dimethylamino)cyclopropyl)methanol (550 mg, 4.77 mmol), 4-nitropyrazole (648 mg, 5.73 mmol) and _PPh3 (1.8 g, 7.16 mmol) in THF (6 mL) under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and purified by silica gel column chromatography eluting with EA in PE (0% to 30%). The fractions with the desired mass signal were combined and concentrated under vacuum to give the desired product, N,N-dimethyl-1-((4-nitro-1H-pyrazol-1-yl)methyl)cyclopropan-1-amine (400 mg, 39.8% yield). LCMS (ESI-MS) m/z = 211.1 [M+H] ⁺ . Step 3 : 1-((1-( dimethylamino ) cyclopropyl ) methyl )-1H- pyrazol -4- amine

Fe (1.0 g, 19.0 mmol) was added to a solution of N,N-dimethyl-1-((4-nitro-1H-pyrazol-1-yl)methyl)cyclopropan-1-amine (400 mg, 1.90 mmol) and NH ₄ Cl (407 mg, 7.61 mmol) in a mixture of EtOH (3 mL) and H ₂ O (1 mL). The resulting mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, the resulting mixture was filtered and the filter cake was washed with ethanol (2×10 mL). The filtrate was concentrated under reduced pressure to give crude 1-((1-(dimethylamino)cyclopropyl)methyl)-1H-pyrazol-4-amine (300 mg, 87.5% yield). LCMS (ESI-MS) m / z = 181.1 [M+H] ⁺ . Intermediate 22 : 2- Cyclopropylisoindolin - 5 - amine Reaction Scheme Detailed procedure Step 1 : 2- cyclopropyl -5- nitroisoindole

To a solution of 5-nitro-2,3-dihydro-1H-isoindole (2.6 g, 15.8 mmol), AcOH (1.90 g, 31.6 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (11.04 g, 63.3 mmol) in THF (100 mL) and MeOH (10 mL) at 20°C, _NaBH3CN (1.49 g, 23.7 mmol) was added. The resulting mixture was stirred at 60°C for 18 h. The reaction mixture was cooled to room temperature and quenched with _1N HCl and extracted with EtOAc. The aqueous layer was basified with solid _K2CO3 to pH = 10 and extracted with DCM. The combined organic phases were washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give 2-cyclopropyl-5-nitroisoindolin (2 g, 49.47%). LCMS (ESI-MS) m/z = 205.1 [M+H] ⁺ . Step 2 : 2 -cyclopropylisoindolin -5- amine

Pd/C (14.59 mg, 0.14 mmol) was added to a solution of 2-cyclopropyl-5-nitroisoindoline (350 mg, 1.7 mmol) in MeOH (5 mL) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a hydrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with MeOH (4×10 mL). The combined filtrate was concentrated under reduced pressure to give the crude product 2-cyclopropylisoindoline-5- amine (270 mg, 88.6% yield). LCMS (ESI-MS) m/z = 175.1 [M+H] ⁺ . Intermediate 23 : 1-(( cyclopentylmethyl ) sulfonyl ) piperidin - 4 - amine Step 1 : (1-(( cyclopentylmethyl ) sulfonyl ) piperidin -4- yl ) carbamic acid tert-butyl ester

To a solution of cyclopentylmethanesulfonyl chloride (470 mg, 2.57 mmol) and DIEA (831.41 mg, 6.43 mmol) in DCM (10 mL) at 0 °C was added tert-butyl N-(piperidin-4-yl)carbamate (429.45 mg, 2.14 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (200 mL) and extracted with _CH2Cl2 (3 x ₂₅₀ mL). The combined organic layers were dried over _{anhydrous Na2SO4 .} After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (1-((cyclopentylmethyl)sulfonyl)piperidin-4-yl)carbamate (800 mg, 96.9% yield). LCMS (ESI-MS) m/z = 347.2 [M+H] ⁺ . Step 2 : 1-(( cyclopentylmethyl ) sulfonyl ) piperidin -4- amine

A solution of tributyl (1-((cyclopentylmethyl)sulfonyl)piperidin-4-yl)carbamate (400 mg, 1.15 mmol) and TFA (3 mL) in DCM (10 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give 1-((cyclopentylmethyl)sulfonyl)piperidin-4-amine (350 mg crude). LCMS (ESI-MS) m/z = 247.1 [M+H] ⁺ . 8- Chloro -N-(1-(( cyclopentylmethyl ) sulfonyl ) piperidin -4- yl )-6 -methylpyrido [3,4-d] pyrimidin -2- amine

A mixture of 1-cyclopentylmethanesulfonylpiperidin-4-amine (350 mg, 1.42 mmol), 8-chloro-2-methanesulfonyl-6-methylpyrido[3,4-d]pyrimidine (366.1 mg, 1.42 mmol) and K ₂ CO ₃ (588.98 mg, 4.26 mmol) in DMSO (3 mL) was stirred at 100 °C for 1 h. The reaction mixture was diluted with water (150 mL) and extracted with DCM (3×150 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under vacuum to give crude 8-chloro-N-(1-((cyclopentylmethyl)sulfonyl)piperidin-4-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine (300 mg). LCMS (ESI-MS) m/z = 424.1 [M+H] ⁺ . Intermediate 24 : 1- cyclopropylcyclobutane -1,3- diol Step 1 : 3-( Benzyloxy )-1- cyclopropylcyclobutan -1- ol

To a stirred solution of 3-(benzyloxy)-1-cyclopropylcyclobutan-1-ol (3 g, 17.0 mmol) in THF (30 mL) was added dropwise 1 M cyclopropylmagnesium bromide in THF (20.43 mL, 20.4 mmol) at -20 °C under nitrogen atmosphere. The mixture was stirred at -20 °C for 30 min. The reaction was quenched by the addition of saturated aqueous NH ₄ Cl solution (30 mL) at 0 °C. The resulting mixture was extracted with EA (3×30 mL), dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE/EA (3:1) to give 3-(benzyloxy)-1-cyclopropylcyclobutan-1-ol (1.6 g, 43.0% yield). LCMS (ESI-MS) m/z = 219.1 [M+H] ⁺ . Step 2 : (3-( benzyloxy )-1 -cyclopropylcyclobutoxy ) trimethylsilane

_Et3N (1.95 g, 19.2 mmol) was added to a mixture of 3-(benzyloxy)-1-cyclopropylcyclobutan-1-ol (1.4 g, 6.4 mmol), TMSCl (1.05 g, 9.6 mmol) and DMAP (0.08 g, 0.64 mmol) in DCM (20 mL). The mixture was stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous _NH4Cl solution (30 mL) at room temperature. The resulting mixture was extracted with DCM (3×30 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE/EA (8:1) to give (3-(benzyloxy)-1-cyclopropylcyclobutoxy)trimethylsilane (700 mg, 37.5% yield). LCMS (ESI-MS) m/z = 291.2 [M+H] ⁺ . Step 3 : 1- cyclopropylcyclobutane -1,3- diol

Pd/C (50 mg, 0.47 mmol) was added to (3-(benzyloxy)-1-cyclopropylcyclobutoxy)trimethylsilane (200 mg, 0.69 mmol) in MeOH (5 mL) under nitrogen atmosphere. The mixture was stirred at room temperature overnight under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (3×30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA 1:2) to give 1-cyclopropylcyclobutane-1,3-diol (50 mg, 56.6% yield). LCMS (ESI-MS) m/z = 129.1 [M+H] ⁺ . Intermediate 25 : 1-( Difluoromethyl )-3- hydroxycyclobutyl benzoate Reaction Scheme Detailed Procedure Step 1 : 3-( Benzyloxy )-1-( difluoromethyl ) cyclobutan -1- ol

To a solution of 3-(benzyloxy)cyclobutan-1-one (10 g, 56.74 mmol) in THF (100 mL) was added (difluoromethyl)trimethylsilane (8.46 g, 68.09 mmol), HMPA (101.70 g, 567.49 mmol) and CsF (8.62 g, 56.74 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (500 mL) and extracted with EA (2×500 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 5:1) to give 3-(benzyloxy)-1-(difluoromethyl)cyclobutan-1-ol (3.5 g, 27.0% yield) as a colorless oil. LCMS (ESI-MS) m/z = 229.1 [M+H] ⁺ . Step 2 : 3-( benzyloxy )-1-( difluoromethyl ) cyclobutyl benzoate

A solution of 3-(benzyloxy)-1-(difluoromethyl)cyclobutan-1-ol (3.4 g, 14.89 mmol) in DCM (30 mL) was treated with Et ₃ N (4.52 g, 44.69 mmol) at 0 °C for 3 min. Then benzoyl chloride (2.30 g, 16.38 mmol) was added portionwise at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (200 mL) and extracted with DCM (3×200 mL). The combined organic layers were washed with saturated sodium chloride solution (2×200 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 1:1) to give 3-(benzyloxy)-1-(difluoromethyl)cyclobutyl benzoate (1 g, 20.2% yield) as a colorless oil. LCMS (ESI-MS) m/z = 333.1 [M+H] ⁺ . Step 3 : 1-( Difluoromethyl )-3- hydroxycyclobutyl benzoate

Pd/C (200 mg, 10%/carbon) was added to a solution of 3-(benzyloxy)-1-(difluoromethyl)cyclobutyl benzoate (800 mg, 2.40 mmol) in MeOH (10 mL) under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product 1-(difluoromethyl)-3-hydroxycyclobutyl benzoate (583.1 mg, 90.0% yield) as a colorless oil. ¹ H NMR (400 MHz, chloroform-d) δ 8.12-8.03 (m, 2H), 7.63-7.59 (m, 1H), 7.49-7.45 (m, 2H), 6.46-6.17 (m, 1H), 4.28-4.21 (m, 1H), 3.26-3.14 (m, 3H), 2.48-2.43 (m, 2H). LCMS (ESI-MS) m/z = 243.0 [M+H] ⁺ . Intermediate 26 : Reaction Scheme of 2- Hydroxy -5- oxa -8- azaspiro [3.5] nonane -8- carboxylic acid tributyl ester Detailed procedure Step 1 : ((3 -methylenecyclobutoxy ) methyl ) benzene

To a stirred mixture of methyltriphenylphosphonium bromide (3.24 g, 90.79 mmol) in THF (100 mL) at room temperature was added t-BuOK (1.14 g, 102.14 mmol). The reaction mixture was stirred at room temperature for 3 h. 3-(Benzyloxy)cyclobutan-1-one (10 g, 56.74 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with water (300 mL) and extracted with diethyl ether (3×300 mL). The combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography (PE/EA, 96:4) to give ((3-methylenecyclobutoxy)methyl)benzene (1.8 g, 18.2% yield) as a colorless oil. LCMS (ESI-MS) m/z = 175.1 [M+H] ⁺ . Step 2 : Tributyl (2-(3-( benzyloxy )-1-( iodomethyl ) cyclobutoxy ) ethyl ) carbamate

To a solution of tributyl N-(2-hydroxyethyl)carbamate (7.77 g, 48.20 mmol) and ((3-methylenecyclobutoxy)methyl)benzene (7 g, 40.17 mmol) in MeCN (70 mL) was added 1-iodo-5-pyrrolidinedione (1.08 g, 48.20 mmol) and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (3 x 100 mL). The combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography (PE/EA, 85:15) to give tert-butyl (2-(3-(benzyloxy)-1-(iodomethyl)cyclobutoxy)ethyl)carbamate (2 g, 41.9% yield) as a colorless oil. LCMS (ESI-MS) m/z = 462.1 [M+H] ⁺ . Step 3 : tert-butyl 2-( benzyloxy )-5- oxa -8- azaspiro [3.5] nonane -8- carboxylate

To a solution of tributyl (2-(3-(benzyloxy)-1-(iodomethyl)cyclobutoxy)ethyl)carbamate (7.2 g, 15.60 mmol) in anhydrous THF (70 mL) cooled to 0 °C was added NaH (0.75 g, 31.21 mmol, 60% in mineral oil). The mixture was stirred at room temperature for 2 h. The reaction was quenched with aqueous NH ₄ Cl solution (100 mL) and extracted with EA (3×200 mL). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA/PE, 20:80) to give tert-butyl 2-(benzyloxy)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate (3 g, 57.7% yield) as a colorless oil. LCMS (ESI-MS) m/z = 334.1 [M+H] ⁺ . Step 4 : tert-butyl 2 - hydroxy -5- oxa -8- azaspiro [3.5] nonane -8- carboxylate

A solution of Pd/C (2.87 g, 26.99 mmol, 10%/carbon) and tert-butyl 2-(benzyloxy)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate (3 g, 8.99 mmol) in MeOH (30 mL) was stirred at room temperature overnight under hydrogen atmosphere. The reaction was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE/EA, 70:30) to give tert-butyl 2-hydroxy-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate (2 g, 91.4% yield) as a colorless oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 5.08 (dd, J = 41.6, 5.7 Hz, 1H), 4.26-3.70 (m, 1H), 3.45 (q, J = 4.7 Hz, 2H), 3.33 (d, J = 23.4 Hz, 1H), 3.28-3.19 (m, 2H), 3.19-3.11 (m, 1H), 2.33-2.26 (m, 1H), 2.25-2.17 (m, 1H),1.80-1.66 (m, 2H), 1.40 (s, 9H). Intermediate 27 : 8,8- difluoro -2- hydroxy -6- azaspiro [3.4] octane -6- carboxylic acid tributyl ester reaction process Detailed procedure Step 1 : 2-((3-( Benzyloxy ) cyclobutylene ) methyl )-4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolanecyclopentane

To a solution of 2,2,6,6-tetramethylpiperidine (9.62 g, 68.09 mmol) in anhydrous THF (100 mL) cooled to -30 °C under _N2 atmosphere, n-BuLi (2.5 M, 27.2 mL) was added dropwise. The mixture was stirred at -30 °C for 0.5 h. The reaction was then cooled to -78 °C and a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)methane (15.21 g, 56.74 mmol) in 50 mL anhydrous THF was added dropwise. The reaction mixture was stirred at -78 °C for 0.5 h and a solution of 3-(benzyloxy)cyclobutan-1-one (10 g, 56.74 mmol) in 50 mL anhydrous THF was added dropwise. The reaction mixture was then warmed to 20°C and stirred for another 12 h. The reaction mixture was slowly poured into 20 mL of saturated NH ₄ Cl aqueous solution at 0°C, and after stirring for 1 h, the solution was diluted with H ₂ O (200 mL) and extracted with EtOAc (400 mL×3). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2-((3-(benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane cyclopentane (13.7 g crude material), which was used without further purification. LCMS (ESI-MS) m/z = 301.1 [M+H] ⁺ . Step 2 : 6- Benzyl -2-( benzyloxy )-8-(4,4,5,5 -tetramethyl - 1,3,2- dioxaborolacyclopentan - 2 - yl ) -6- azaspiro [ 3.4] octane

A solution of 2-((3-(Benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.7 g crude), N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (13.00 g, 54.76 mmol) and LiF (3.55 g, 136.90 mmol) in DMSO (200 mL) was stirred at 110 °C for 1 h. The reaction mixture was diluted with _H2O (200 mL) and extracted with EA (1000 mL). The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure to give crude 6-benzyl-2-(benzyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolacyclopentan-2-yl)-6-azaspiro[3.4]octane (20 g) as a colorless oil, which was used in the next step without further purification. LCMS (ESI-MS) m/z = 434.2 [M+H] ⁺ . Step 3 : 6- Benzyl -2-( benzyloxy )-6- azaspiro [ 3.4] octan -8- ol

A solution of 6-benzyl-2-(benzyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolacyclopentan-2-yl)-6-azaspiro[3.4]octane (20 g crude), sodium perborate (4.53 g, 55.37 mmol) and LiOH (3.32 g, 138.44 mmol) in THF (50 mL) and H ₂ O (200 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with H ₂ O (200 mL) and extracted with EA (3×500 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH/DCM, 3:97) to obtain 6-benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-ol (10 g, 67.0%) as a colorless oil. LCMS (ESI-MS) m/z = 324.1 [M+H] ⁺ . Step 4 : 6- Benzyl -2-( benzyloxy )-6- azaspiro [3.4] octan -8- one

To a solution of oxalyl chloride (7.85 g, 61.8 mmol) in DCM (100 mL) cooled to -78 °C under nitrogen atmosphere, a solution of DMSO (4.83 g, 61.8 mmol) in DCM (20 mL) was added dropwise. The mixture was stirred at -78 °C for 20 min. A solution of 6-benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-ol (10 g, 30.9 mmol) in DCM (20 mL) was then added dropwise and the mixture was stirred for 20 min. Et ₃ N (12.5 g, 123 mmol) was added dropwise and the mixture was stirred for 20 min. The reaction mixture was diluted with water (200 mL) and extracted with DCM (3×200 mL). The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0 to 10%). The fractions with the desired mass signal were combined and concentrated under reduced pressure to give 6-benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-one (5.8 g, 58.4% yield). LCMS (ESI-MS) m/z = 322.2 [M+H] ⁺ . Step 5 : 6- Benzyl -2-( benzyloxy )-8,8 -difluoro -6- azaspiro [3.4] octane

DAST (8.73 g, 54.1 mmol) was added to a solution of 6-benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-one (5.8 g, 18.0 mmol) in DCM (60 mL) at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0% to 10%). The fractions with the desired mass signal were combined and concentrated under reduced pressure to give 6-benzyl-2-(benzyloxy)-8,8-difluoro-6-azaspiro[3.4]octane (1.2 g, 19.4% yield). LCMS (ESI-MS) m/z = 344.2 [M+H] ⁺ . Step 6 : 8,8- difluoro -2- hydroxy -6- azaspiro [3.4] octane -6- carboxylic acid tributyl ester

Pd(OH) ₂ /C (0.49 g, 3.49 mmol) was added to a solution of 6-benzyl-2-(benzyloxy)-8,8-difluoro-6-azaspiro[3.4]octane (1.2 g, 3.49 mmol), _Boc2O (0.92 g, 4.19 mmol) and _Et3N (1.06 g, 10.48 mmol) in MeOH (120 mL). The resulting mixture was stirred under _H2 atmosphere at room temperature for 5 days. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH in DCM, 0% to 5%). The fractions with the desired mass signal were combined, concentrated under reduced pressure and lyophilized to give tributyl 8,8-difluoro-2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (500 mg, 54.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 5.3-5.06 (m, 1H), 4.20-4.00 (m, 1H), 3.69-3.50 (m, 3H), 3.47-3.39 (m, 2H), 2.14-2.10 (m, 1H), 2.04-1.96 (m, 1H), 1.93-1.85 (m, 1H), 1.40 (s, 9H). Intermediate 28 : 6- Benzyl 2-( tert-butyl ) 8-( difluoromethyl )-2,6 -diazaspiro [3.4] octane -2,6- dicarboxylate Step 1 : 6- Benzyl 2-( tert-butyl ) 8- methyl 2,6 -diazaspiro [3.4] octane -2,6,8- tricarboxylate

CbzCl (1.14 g, 6.65 mmol) and Et ₃ N (0.90 g, 8.87 mmol) were added to a solution of 2-(tert-butyl) 8-methyl 2,6-diazaspiro[3.4]octane-2,8-dicarboxylate (1.2 g, 4.43 mmol) in DCM (20 mL) cooled to 0°C. The reaction mixture was stirred for 30 minutes, then warmed to room temperature and stirred for 1 h. The reaction was quenched with water (200 mL). The resulting mixture was extracted with CH ₂ Cl ₂ (3×200 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 1:1) to give 6-benzyl 2-(tert-butyl) 8-methyl 2,6-diazaspiro[3.4]octane-2,6,8-tricarboxylate (1.5 g, 83.6% yield). LCMS (ESI-MS) m/z = 305.1 [M+H-100] ⁺ . Step 2 : 6- benzyl 2-( tert-butyl ) 8-( hydroxymethyl )-2,6 -diazaspiro [3.4] octane -2,6 -dicarboxylate

_NaBH4 (74.83 mg, 1.97 mmol) was added to a solution of 6-benzyl 2-(tert-butyl) 8-methyl 2,6-diazaspiro[3.4]octane-2,6,8-tricarboxylate (200 mg, 0.49 mmol) in MeOH (3 mL). The reaction mixture was stirred at room temperature for 1 h and quenched with water (20 mL). The resulting mixture was extracted with EA (3×20 mL). The combined organic layers were dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure and used as is in the next step. LCMS (ESI-MS) m/z =277.1 [M+H-100] ⁺ . Step 3 : 6- Benzyl 2-( tert-butyl ) 8- formyl -2,6- diazaspiro [3.4] octane -2,6- dicarboxylate

Dess-Martin (581.37 mg, 1.37 mmol) was added to a mixture of 6-benzyl 2-(tert-butyl) 8-(hydroxymethyl)-2,6-diazaspiro[3.4]octane-2,6-dicarboxylate (430 mg, 1.14 mmol) in DCM (8 mL). The resulting mixture was stirred at room temperature for 1 h and filtered. The filter cake was washed with _CH2Cl2 ( ₃₀ mL) and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA, 1:3) to give 6-benzyl 2-(tert-butyl) 8-formyl-2,6-diazaspiro[3.4]octane-2,6-dicarboxylate (240 mg, 56.1% yield). LCMS (ESI-MS) m/z = 275.1 [M+H-100] ⁺ . Step 4 : 6- benzyl 2-( tert-butyl ) 8-( difluoromethyl )-2,6- diazaspiro [3.4] octane -2,6- dicarboxylate

DAST (206.63 mg, 1.28 mmol) was added to a mixture of 6-benzyl 2-(tert-butyl) 8-formyl-2,6-diazaspiro[3.4]octane-2,6-dicarboxylate (240 mg, 0.64 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 1 h and quenched with water (20 mL). The resulting mixture was extracted with CH ₂ Cl ₂ (2×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA, 1:3) to give 6-benzyl 2-(tert-butyl) 8-(difluoromethyl)-2,6-diazaspiro[3.4]octane-2,6-dicarboxylate (160 mg, 63.0% yield). LCMS (ESI-MS) m/z = 297.1 [M+H-100] ⁺ . Step 5 : Benzyl 8-( difluoromethyl )-2,6 -diazaspiro [3.4] octane -6- carboxylate

A solution of 6-benzyl 2-(tert-butyl) 8-(difluoromethyl)-2,6-diazaspiro[3.4]octane-2,6-dicarboxylate (130 mg, 0.32 mmol) in TFA (0.3 mL) and DCM (0.9 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and used as is in the next step. LCMS (ESI-MS) m/z = 297.1 [M+H] ⁺ . Example Compound Example 2 : 8-(2,2 -Difluoro -6- azaspiro [3.4] octan -6- yl ) -N- (1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine Reaction Scheme Detailed procedure Step 1 : 8-(2,2 -difluoro -6- azaspiro [3.4] octan -6- yl )-2-( methylthio ) pyrido [3,4-d] pyrimidine

To a stirred mixture of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (900 mg, 4.25 mmol) and 2,2-difluoro-6-azaspiro[3.4]octane hydrochloride (780.4 mg, 4.25 mmol) in acetonitrile (10 mL) was added N , N -diisopropylethylamine (1.65 g, 12.75 mmol). The resulting mixture was heated to 100 °C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the crude product 8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine (880 mg). The crude product was used directly in the next step without further purification.

LCMS (ESI) m/z = 323 [M+H] ⁺ . Step 2 : 8-(2,2 -difluoro -6- azaspiro [3.4] octan -6- yl )-2-( methylsulfonyl ) pyrido [3,4-d] pyrimidine

To a stirred solution of 8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine (780 mg, 2.42 mmol) in dichloromethane (20 mL) was added 3-chloroperoxybenzoic acid (1.04 g, 6.05 mmol). The resulting mixture was stirred at room temperature overnight and concentrated under vacuum to give crude 8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (910 mg), which was used directly in the next step without further purification. LCMS (ESI) m/z= 355 [M+H] ⁺ . Step 3 : 8-(2,2 -difluoro -6- azaspiro [3.4] octan -6- yl )-N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine

To a stirred mixture of 8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (150 mg, 0.42 mmol) and 1-(methylsulfonyl)piperidin-4-amine (75.45 mg, 0.42 mmol) in dimethyl sulfoxide (2 mL) was added N , N -diisopropylethylamine (164.12 mg, 1.26 mmol). The resulting mixture was heated to 100 °C and stirred overnight. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to give the crude product. The crude product was purified by preparative reverse phase HPLC (acetonitrile/water (with ₁₀ mM _NH4HCO3 and 0.1% _NH3.H2O ) _gradient ) to give the title compound (48.9 mg, 23.8% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.99 (s, 1H), 7.73 (d, J = 5.6 Hz, 1H), 7.52 (s, 1H), 6.81 (d, J = 5.2 Hz, 1H), 4.10 (s, 2H), 3.89 (s, 3H), 3.59 (d, J = 12.4 Hz, 2H), 2.93-2.86 (m, 5H), 2.75-2.56 (m, 4H), 2.13-1.96 (m, 4H), 1.69-1.56 (m, 2H). LCMS (ESI) m/z = 453 [M+H] ⁺ . Example 6 : 8-(2,2 -difluoro -6- azaspiro [3.4] octan -6- yl ) -N- (5-(6- ethyl -2,6- diazaspiro [3.3] hept -2- yl ) pyridin -2- yl ) pyrido [3,4- d ] pyrimidin -2- amine

To a stirred mixture of N- (5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)carboxamide (50 mg, 0.20 mmol) in tetrahydrofuran (2 mL) at 0°C was added sodium hydroxide (60% in mineral oil, 24 mg, 0.60 mmol). The resulting mixture was stirred at 0°C for 15 minutes. Then 8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (78 mg, 0.22 mmol) was added to the mixture, and the resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was purified by preparative reverse phase HPLC (acetonitrile/water (with 10 mM _NH4HCO3 and 0.1% _NH3.H2O ) _gradient ) to give _the title compound (12.7 mg, 10.0% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 9.13 (s, 1H), 7.94-7.62 (m, 3H), 7.14-6.97 (m, 2H), 4.39 (s, 4H), 4.12-4.18 (m, 6H), 3.98-3.92 (m, 2H), 3.27-3.25 (m, 2H), 2.67-2.61 (m, 4H), 2.16-2.13 (m, 2H), 1.42-1.34 (m, 1H), 1.31-1.23 (m, 3H). LCMS (ESI) m/z = 493 [M+H] ⁺ . Example 6 : 8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-2-amine Step 1 : 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tributyl ester

To a stirred mixture of tributyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (5 g, 25.21 mmol) and 5-fluoro-2-nitropyridine (5.37 g, 37.82 mmol) in dimethylsulfoxide (30 mL) was added N , N -diisopropylethylamine (9.78 g, 75.65 mmol). The resulting mixture was heated to 80 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the crude product. The residue was purified by trituration with petroleum ether/ethyl acetate (5:1, 100 mL) to give tributyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (6.78 g, 83.7% yield) as a yellow solid.

LCMS (ESI) m/z = 321 [M+H] ⁺ . Step 2 : 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

To a stirred mixture of tributyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (6.78 g, 21.16 mmol) in dichloromethane (80 mL) was added trifluoroacetic acid (16 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The residue was diluted with dichloromethane (100 mL) and concentrated again under vacuum to give crude 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (6 g) as a tan solid. The crude product was used directly in the next step without further purification.

LCMS (ESI) m/z = 221 [M+H] ⁺ . Step 3 : 2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

A solution of 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (6 g, 18.9 mmol) in methanol (100 mL) was treated with triethylamine (5.73 g, 56.7 mmol) for 10 minutes, followed by the addition of acetaldehyde (4.16 g, 94.5 mmol), acetic acid (0.23 mL, 4.08 mmol) and sodium cyanoborohydride (2.51 g, 39.8 mmol). The resulting mixture was stirred at room temperature for 3 hours and concentrated under vacuum. The residue was diluted with water (500 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by trituration with dichloromethane (100 mL) to give 2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (4 g, 58.9% yield) as an orange solid. LCMS (ESI) m/z = 249 [M+H] ⁺ . Step 4 : 5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-amine

A solution of 2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (4 g, 16.11 mmol), ammonium chloride (4.31 g, 80.55 mmol), iron powder (9.00 g, 161.100 mmol) and water (20 mL) in ethanol (60 mL) was stirred at 80 °C for 1 hour. The resulting mixture was filtered and the filter cake was washed with ethanol (100 mL). The filtrate was concentrated under vacuum to give the crude product. The residue was purified by reverse phase flash chromatography (C18 silica gel, acetonitrile/water (with 10 mmol/L _NH4HCO3 ) _gradient ) to give 5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-amine (2 g, 56.6% yield) as a black solid.

LCMS (ESI) m/z = 219 [M+H] ⁺ . Step 5 : N- (5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)formamide

A solution of acetic anhydride (2 mL) in formic acid (4 mL) was stirred at room temperature for 1 hour, followed by the addition of 5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-amine (400 mg, 1.83 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution (200 mL) to pH = 7 and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was purified by preparative reverse phase HPLC (acetonitrile/water (with 10 mM _NH4HCO3 and 0.1% _NH3.H2O ) gradient) to give the title compound as an off-white solid (70 mg, _15.3 % yield). LCMS (ESI) m/ _z = 247 [M+H] ⁺ . Step 6 : 8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl) -N- (5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-2-amine

To a stirred mixture of N- (5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)carboxamide (50 mg, 0.20 mmol) in tetrahydrofuran (2 mL) at 0°C was added sodium hydroxide (60% in mineral oil, 24 mg, 0.60 mmol). The resulting mixture was stirred at 0°C for 15 minutes. Then 8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (78 mg, 0.22 mmol) was added to the mixture, and the resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was _concentrated under vacuum and the residue was purified by preparative reverse phase HPLC (acetonitrile/water (with 10 mM _NH4HCO3 and 0.1% _NH3.H2O ) _gradient ) to give the title compound (12.7 mg, 10.0% yield) as an orange solid.

LCMS (ESI) m/z = 493 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 9.13 (s, 1H), 7.94-7.62 (m, 3H), 7.14-6.97 (m, 2H) ,4.39 (s, 4H), 4.12- 4.18 (m, 6H), 3.98-3.92 (m, 2H), 3.27-3.25 (m, 2H), 2.67-2.61 (m, 4H), 2.16-2.13 (m, 2H), 1.42-1.34 (m, 1H ), 1.31-1.23 (m, 3H). Example 11 : 8-(8,8 -difluoro -2-( methyl -d3)-2,6 -diazaspiro [3.4] octan -6- yl )-6- methyl -N-(1- ((1- methyl -1H- pyrazol -4- yl ) sulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine reaction scheme

Iodomethane _- d3 (9.51 mg, 0.06 mmol) was added to a mixture of 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine ( ₇₀ mg, 0.13 mmol) and _K2CO3 (36.3 mg, 0.26 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 30 min, quenched by the addition of water (5 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine (10 mL), dried over _{anhydrous Na2SO4} , filtered and the filtrate was concentrated under reduced pressure to give a crude product. The residue was purified by preparative TLC (MeOH/DCM = 1:10) to give the desired product 8-(8,8-difluoro-2-(methyl-d3)-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (23.6 mg, 32.0% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.96 (s, 1H), 8.34 (s, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 6.76 (s, 1H), 4.33-4.24 (m, 2H), 4.23-4.15 (m, 1H), 3.92 (s, 3H), 3.70 (s, 1H), 3.60-3.50 (m, 2H), 3.31-3.25 (m, 2H), 3.18-2.99 (m, 2H), 2.49-2.40 (m, 3H), 2.33 (s, 3H), 2.08-1.97 (m, 2H), 1.70-1.54 (m, 2H). LCMS (ESI-MS) m/z = 551.3 [M+H] ⁺ . Example 12 : 8-(8,8 -difluoro -2-( methyl -d3)-2,6 -diazaspiro [3.4] octan -6- yl )-6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine Reaction Scheme Detailed procedure Step 1 : 6- Benzyl 2-( tert-butyl ) 8,8- difluoro -2,6 -diazaspiro [3.4] octane -2,6- dicarboxylate

Benzyl chloroformate (412 mg, 2.42 mmol) was added to a solution of tributyl 8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate (500 mg, 2.01 mmol) and _Et3N (408 mg, 4.03 mmol) in DCM (6 mL) cooled to 0°C. The resulting mixture was stirred at 0°C for 30 minutes and then warmed to room temperature and stirred for another hour. The resulting mixture was quenched by the addition of water (15 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (PE/EA, 2:1) to give the desired product 6-benzyl 2-(tert-butyl) 8,8-difluoro-2,6-diazaspiro[3.4]octane-2,6-dicarboxylate (700 mg, 90.9% yield). LCMS (ESI-MS) m/z = 383.2 [M+H] ⁺ . Step 2 : Benzyl 8,8- difluoro -2,6 -diazaspiro [3.4] octane -6- carboxylate

TFA (2 mL) was added to a stirred mixture of 6-benzyl 2-(tert-butyl) 8,8-difluoro-2,6-diazaspiro[3.4]octane-2,6-dicarboxylate (500 mg, 1.31 mmol) in DCM (6 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under high vacuum to give the crude product (350 mg). The crude product was used in the next step without further purification. LCMS (ESI-MS) m/z = 283.2 [M+H] ⁺ . Step 3 : Benzyl 8,8- difluoro -2-( methyl- d ₃ )-2,6 -diazaspiro [3.4] octane -6- carboxylate

Iodomethane _- d3 (64.2 mg, 0.44 mmol) was slowly added to a mixture of 8,8-difluoro-2,6-diazaspiro[3.4]octane-6-carboxylic acid benzyl ester (250 mg, 0.89 mmol) and _K2CO3 (245 mg, 1.77 mmol) in DMF (3 mL). The resulting mixture was stirred at room temperature for ₁ hour, quenched with water (8 mL) and extracted with DCM (3×8 mL). The combined organic layers were washed with brine (15 mL), dried over _{anhydrous Na2SO4} , filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (PE/EA, 1:1) to give the desired product 8,8-difluoro-2-(methyl- d ₃ )-2,6-diazaspiro[3.4]octane-6-carboxylic acid benzyl ester (90 mg, 33.9% yield). LCMS (ESI-MS) m/z = 300.3 [M+H] ⁺ . Step 4 : 8,8- difluoro -2-( methyl - d ₃ )-2,6 -diazaspiro [3.4] octane

Pd/C (10%/carbon, 10 mg) was added to a mixture of 8,8-difluoro-2-(methyl _- d3 )-2,6-diazaspiro[3.4]octane-6-carboxylic acid benzyl ester (70 mg, 0.23 mmol) in MeOH (4 mL) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 0.5 h under hydrogen atmosphere. The reaction mixture was _filtered and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to give the crude product 8,8-difluoro-2-(methyl- d3 )-2,6-diazaspiro[3.4]octane (60 mg) as a colorless oil. The crude product was used in the next step without further purification. LCMS (ESI-MS) m/z = 166.2 [M+H] ⁺ . Step 5 : 8-(8,8 -difluoro -2-( methyl -d3)-2,6 -diazaspiro [3.4] octan -6- yl )-6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine

Pd-PEPPSI-iHeptCl 3-chloropyridine (13.7 mg, 0.014 mmol) was added to a mixture of 8-chloro-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (50 mg, 0.141 mmol), 8,8-difluoro- _2- (methyl- d3 )-2,6-diazaspiro[3.4]octane (23.2 mg, 0.141 mmol) and _Cs2CO3 ( _91.6 mg, 0.28 mmol) in 1,4-dioxane (1 mL) under nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was filtered and the filter cake was washed with DCM (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH, 10:1). The product was further purified by preparative RP-HPLC to give the desired product 8-(8,8-difluoro-2-(methyl-d3)-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (2.7 mg, 3.79% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.98 (s, 1H), 7.54 (s, 1H), 6.78 (s, 1H), 4.40-4.22 (m, 4H), 3.90-3.79 (m, 1H), 3.61 (d, J = 11.6 Hz, 3H), 3.26-3.15 (m, 3H), 2.97-2.84 (m, 5H), 2.34 (s, 3H), 2.13-1.98 (m, 2H), 1.69-1.55 (m, 2H). LCMS (ESI-MS) m/z = 485.3 [M+H] ⁺ . Example 39 : N-(6- fluoro -2-( methylsulfonyl ) isoindolin -5- yl )-6- methyl -8-(2,6 -diazaspiro [3.4] octan -2- yl ) pyrido [3,4-d] pyrimidin -2- amine Reaction Scheme Detailed procedure Step 1 : 2-(2-((6- fluoro -2-( methylsulfonyl ) isoindolin -5- yl ) amino )-6- methylpyrido [3,4-d] pyrimidin -8- yl )-2,6 -diazaspiro [3.4] octane -6- carboxylic acid tributyl ester

To a solution of 8-chloro-N-(6-fluoro-2-(methylsulfonyl)isoindolin-5-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine (65 mg, 0.16 mmol) in dimethylsulfoxide (5 mL) was added tributyl 2,6-diazaspiro[3.4]octane-6-carboxylate (67.67 mg, 0.31 mmol) and K ₂ CO ₃ (66.56 mg, 0.47 mmol). The resulting mixture was stirred at 100 °C for 3 h under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with EA (200 mL) and washed with saturated aqueous sodium chloride solution (3×200 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give 2-(2-((6-fluoro-2-(methylsulfonyl)isoindolin-5-yl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid tributyl ester (60 mg, 64.5% yield). LCMS (ESI-MS) m/z = 584.2 [M+H] ⁺ . Step 2 : N-(6- fluoro -2-( methylsulfonyl ) isoindolin -5- yl )-6- methyl -8-(2,6 -diazaspiro [3.4] octan -2- yl ) pyrido [3,4-d] pyrimidin -2- amine

To a solution of tributyl 2-(2-((6-fluoro-2-(methylsulfonyl)isoindolin-5-yl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (55 mg, 0.09 mmol) in DCM (2 mL) was added TFA (0.2 mL). The resulting mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The crude product (55 mg) was purified by preparative RP-HPLC to give N-(6-fluoro-2-(methylsulfonyl)isoindolin-5-yl)-6-methyl-8-(2,6-diazaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine (17.8 mg, 37.70% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.38 (s, 1H), 9.18-9.09 (m, 1H), 7.82-7.55 (m, 1H), 7.32-7.21 (m, 1H), 6.81-6.75 (m, 1H), 4.70-4.60 (m, 5H), 4.15 (s, 4H), 3.10-2.98 (m, 5H), 2.95-2.88 (m, 2H), 2.35 (s, 3H), 2.01-1.95 (m, 2H). LCMS (ESI-MS) m/z = 484.2 [M+H] ⁺ Example 25 : N-(1-( cyclopropylsulfonyl ) piperidin -4- yl )-6- methyl -8-(2,6 -diazaspiro [3.4] octan -2- yl ) pyrido [3,4-d] pyrimidin -2- amine Reaction Scheme Detailed Procedure Step 1 : 2-(2-((1-( cyclopropylsulfonyl ) piperidin -4- yl ) amino )-6- methylpyrido [3,4-d] pyrimidin -8- yl )-2,6 -diazaspiro [3.4] octane -6- carboxylic acid tributyl ester

A solution of 8-chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine (100 mg, 0.26 mmol), tributyl 2,6-diazaspiro[3.4]octane-6-carboxylate (55.59 mg, 0.26 mmol) and K ₂ CO ₃ (108.57 mg, 0.78 mmol) in DMSO (1 mL) was stirred at 100 °C overnight. The resulting mixture was diluted with water (20 mL) and extracted with CH ₂ Cl ₂ (3×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH, 10:1) to give tributyl 2-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (130 mg, 80.11% yield). LCMS (ESI-MS) m/z = 558.3 [M+H] ⁺ . Step 2 : N-(1-( cyclopropylsulfonyl ) piperidin -4- yl )-6- methyl -8-(2,6 -diazaspiro [3.4] octan -2- yl ) pyrido [3,4-d] pyrimidin -2- amine

A solution of tributyl 2-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (120 mg, 0.21 mmol) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by preparative TLC (EA). The product was further purified by preparative RP-HPLC to give N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-methyl-8-(2,6-diazaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine (50.1 mg, 49.56 % yield). ¹ H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 2.7 Hz, 1H), 7.45 (s, 1H), 6.67 (d, J = 6.0 Hz, 1H), 4.25 (s, 4H), 3.81 (s, 1H), 3.63 (d, J = 12.1 Hz, 2H), 3.47(s, 1H), 3.07-2.78 (m, 5H),2.68-2.54 (m, 2H), 2.30 (s, 3H), 2.17-2.07 (m, 1H), 2.06-1.92 (m, 3H), 1.66-1.48 (m, 2H), 1.07-0.86 (m, 4H). LCMS (ESI-MS) m/z = 458.3 [M+H] ⁺ . Example 46 : 1-( Cyclopropanesulfonyl ) -N- (8-{2,6 -diazaspiro [3.4] octan -2- yl }-6-( difluoromethyl ) pyrido [3,4- d ] pyrimidin -2- yl ) piperidin -4- amine Reaction Scheme Step 1 : 2-[6-( difluoromethyl )-2-( methylthio ) pyrido [3,4- d ] pyrimidin -8- yl ]-2,6- diazaspiro [3.4] octane -6- carboxylic acid tributyl ester

A solution of tributyl 2,6-diazaspiro[3.4]octane-6-carboxylate (0.225 g, 1.059 mmol) and anhydrous triethylamine (0.738 ml, 5.293 mmol) in dimethylformamide (5.54 ml) was stirred at room temperature for 5 minutes. Then, 8-chloro-6-(difluoromethyl)-2-(methylthio)pyrido[3,4 -d ]pyrimidine (0.277 g, 1.059 mmol) was added, and the reaction mixture was stirred at 80 °C for 18 h. The reaction mixture was diluted with water (10 mL) and dichloromethane (10 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (10 mL x 3), and the combined organic layers were washed with saturated _{aqueous K2CO3} , dried over anhydrous _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (hexane to hexane/EtOAc 6:4) to provide the title compound (0.389 g, 84% yield). ¹ H NMR (300 MHz, CHLOROFORM-d) δ 9.07 (s, 1H), 7.14 (s, 1H), 6.53 (t, J = 55.8 Hz, 1H), 3.68 - 3.56 (m, 2H), 3.56 - 3.35 (m, 2H), 2.66 (s, 3H), 2.19 (t, J = 7.1 Hz, 2H), 1.58 (s, 4H), 1.50 (s, 9H). UPLC (ESI) [M+H] ⁺ = 438.45. Step 2 : 2-[6-( difluoromethyl )-2 -methanesulfonylpyrido [3,4- d ] pyrimidin -8- yl ]-2,6 -diazaspiro [3.4] octane -6- carboxylic acid tributyl ester

To a solution of tributyl 2-[6-(difluoromethyl)-2-(methylthio)pyrido[3,4- d ]pyrimidin-8-yl]-2,6-diazaspiro[3.4]octane-6-carboxylate (0.389 g, 0.890 mmol) in dichloromethane (11.68 ml), 3-chloroperbenzoic acid (0.768 g, 4.450 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 90 min, quenched by dropwise addition of 10% _{aqueous Na2S2O3} solution (10 mL) and extracted with dichloromethane (10 mL×3). The combined organic layers were washed with saturated aqueous _NaHCO3 solution, _dried over anhydrous _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (hexane/EtOAc 9:1 to hexane/EtOAc 4:6) to provide the title compound (0.326 g, 74%). ¹ H NMR (300 MHz, CHLOROFORM-d) δ 9.42 (s, 1H), 7.27 (s, 1H), 6.55 (t, J = 55.4 Hz, 1H), 3.63 (s, 2H), 3.57 - 3.43 (m, 2H), 3.42 (s, 3H), 2.31 - 2.15 (m, 2H), 1.68 - 1.57 (m, 3H), 1.57 - 1.40 (m, 10H). UPLC (ESI) [M+H] ⁺ = 470.00. Step 3 : 2-(2-{[1-( cyclopropanesulfonyl ) piperidin -4- yl ] amino }-6-( difluoromethyl ) pyrido [3,4- d ] pyrimidin -8- yl )-2,6 -diazaspiro [3.4] octane -6- carboxylic acid tributyl ester

A solution of 1-(cyclopropanesulfonyl)piperidin-4-amine hydrochloride (0.051 g, 0.202 mmol) and anhydrous triethylamine (0.141 ml, 1.012 mmol) in dimethylformamide (2.0 ml) was stirred at room temperature for 5 min. Then, tributyl 2-[6-(difluoromethyl)-2-methanesulfonylpyrido[3,4- d ]pyrimidin-8-yl]-2,6-diazaspiro[3.4]octane-6-carboxylate (0.1 g, 0.202 mmol) was added and the reaction mixture was stirred at 80 °C for 24 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel flash column chromatography (hexane to hexane/EtOAc 4:6) to provide the title compound (0.079 g, 53% yield). ¹ H NMR (300 MHz, CHLOROFORM-d) δ 8.92 (s, 1H), 7.09 (s, 1H), 6.53 (t, J = 56.1 Hz, 1H), 5.33 (s, 1H), 4.01 (s, 1H), 3.81 (d, J = 12.5 Hz, 2H), 3.61 (d, J = 9.7 Hz, 2H), 3.47 (s, 2H), 3.09 (t, J = 11.3 Hz, 2H), 2.33 (tt, J = 8.3, 4.9 Hz, 1H), 2.20 (q, J = 9.4, 7.1 Hz, 4H), 1.86 - 1.54 (m, 6H), 1.5 1.26 - 1.15 (m, 2H), 1.05 (d, J = 6.8 Hz, 2H). UPLC (ESI) [M+H] ⁺ = 594.50. Step 4 : 1-( Cyclopropanesulfonyl ) -N- (8-{2,6- diazaspiro [3.4] octan -2- yl }-6-( difluoromethyl ) pyrido [3,4- d ] pyrimidin -2- yl ) piperidin -4- amine

A solution of tributyl 2-(2-{[1-(cyclopropanesulfonyl)piperidin-4-yl]amino}-6-(difluoromethyl)pyrido[3,4- d ]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (0.079 g, 0.107 mmol) in anhydrous dichloromethane (3.97 ml) was cooled to 0 °C. Then, trifluoroacetic acid (0.79 ml) was added dropwise and the reaction mixture was stirred at 0 °C for 2 h. The volatiles were removed under reduced pressure and the crude material was purified by preparative HPLC (0.1% formic acid) to provide the title compound (0.043 g, 80% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (s, 1H), 8.80 (s, 1H), 7.88 (s, 1H), 7.19 (s, 1H), 6.75 (t, J = 55.5 Hz, 1H), 4.37 (s, 4H), 3.87 (s, 1H), 3.63 (dd, J = 12.5, 4.5 Hz, 2H), 3.36 (s, 2H), 3.22 - 3.14 (m, 2H), 3.11 - 3.01 (m, 2H), 2.60 (tt, J = 7.8, 4.9 Hz, 1H), 2.21 (t, J = 7.2 Hz, 2H), 2.0 12.8 Hz, 2H), 1.63 (q, J = 11.3 Hz, 2H), 1.01 (dt, J = 7.9, 2.8 Hz, 2H), 0.98 - 0.92 (m, 2H). LCMS (ESI) [M+H] ⁺ = 494.3. Example 51 : N-(1-(( cyclopentylmethyl ) sulfonyl ) piperidin -4- yl )-6- methyl -8-(2,6 -diazaspiro [3.4] octan -2- yl ) pyrido [3,4-d] pyrimidin -2- amine Reaction Scheme Step 1 : 2-(2-((1-(( cyclopentylmethyl ) sulfonyl ) piperidin -4- yl ) amino )-6 -methylpyrido [3,4-d] pyrimidin -8- yl )-2,6 -diazaspiro [3.4] octane -6- carboxylic acid tributyl ester

A mixture of 8-chloro-N-(1-((cyclopentylmethyl)sulfonyl)piperidin-4-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine (300 mg, 0.70 mmol), K ₂ CO ₃ (293.39 mg, 2.12 mmol) and tributyl 2,6-diazaspiro[3.4]octane-6-carboxylate (150.22 mg, 0.70 mmol) in DMSO (5 mL) was stirred at 100 °C for 1 h. The reaction mixture was diluted with water (250 mL) and extracted with DCM (3×250 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under vacuum. The crude product was purified by preparative TLC (EA) to give tributyl 2-(2-((1-((cyclopentylmethyl)sulfonyl)piperidin-4-yl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (150 mg, 31.81% yield). LCMS (ESI-MS) m/z = 600.3 [M+H] ⁺ . Step 2 : N-(1-(( cyclopentylmethyl ) sulfonyl ) piperidin -4- yl )-6- methyl -8-(2,6 -diazaspiro [3.4] octan -2- yl ) pyrido [3,4-d] pyrimidin -2- amine

A mixture of tributyl 2-(2-((1-((cyclopentylmethyl)sulfonyl)piperidin-4-yl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (130 mg, 0.21 mmol) and TFA (1 mL) in DCM (3 mL) was stirred at room temperature for 1 h. The residue was purified by preparative TLC (EA) followed by preparative RP-HPLC to give N-(1-((cyclopentylmethyl)sulfonyl)piperidin-4-yl)-6-methyl-8-(2,6-diazaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine (39.5 mg, 34.4% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 7.40 (s, 1H), 6.66 (d, J = 7.9 Hz, 1H), 4.24 (s, 4H), 3.82 (s, 1H), 3.63-3.55 (m, 2H), 3.06 (d, J = 6.9 Hz, 2H), 2.94 (d, J = 14.2 Hz, 4H), 2.84-2.77 (m, 2H), 2.30 (s, 3H), 2.26-2.15 (m, 1H), 2.03-1.91 (m, 4H), 1.90-1.81 (m, 2H), 1.67-1.48 (m, 6H), 1.35-1.21 (m, 3H). LCMS (ESI-MS) m/z = 500.3 [M+H] ⁺ . Example 88 : 1- Cyclopropyl -3-(6- methyl -2-((1-( methylsulfonyl ) piperidin -4- yl ) amino ) pyrido [3,4-d] pyrimidin -8- yl ) cyclobutan -1- ol

To an oven-dried 20 mL vial was charged 1-cyclopropylcyclobutane-1,3-diol (43 mg, 0.49 mmol) and NHC (177 mg, 0.45 mmol). After the vial was evacuated and refilled with a nitrogen atmosphere, METB (4 mL) was added and the reaction was stirred at room temperature for 5 minutes. A mixture of pyridine (81 mg, 1.03 mmol) in METB (1 mL) was added and the mixture was stirred at room temperature for 10 minutes. To another dried 40 mL vial was charged 8-chloro-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (100 mg, 0.28 mmol), NHC (177.72 mg, 0.45 mmol), Ir(ppy) ₂ (dtbbpy) _PF6 (3.85 mg, 0.004 mmol), _NiBr2 (dtbbpy) (6.84 mg, 0.014 mmol) and 1-azabicyclo[2.2.2]octane (54.68 mg, 0.49 mmol) in DMA (5 mL) under nitrogen atmosphere. The mixture was stirred at 800 rpm for 3 h under 450 nm blue LED. The resulting mixture was concentrated under vacuum. The residue was purified by preparative RP-HPLC to give 1-cyclopropyl-3-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)cyclobutan-1-ol (2.1 mg, 1.54%). ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.97-8.95 (m, 2H), 7.29-7.26 (m, 1H), 4.63-4.60 (m, 1H), 4.10-3.83 (m, 3H), 2.99-2.93 (m, 4H), 2.89-2.87 (m, 4H), 2.72-2.70 (m, 3H), 2.54-2.20 (m, 4H), 1.84-1.78 (m, 3H), 0.47-0.41 (m, 4H). LCMS (ESI-MS) m/z = 432.2 [M+H] ⁺ . Example 60 : 6- cyclopropyl -8-(8,8 -difluoro -2,6 -diazaspiro [3.4] octan -6- yl ) -N- (1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4 -d ] pyrimidin -2- amine Reaction Scheme Detailed Procedure Step 1 : 8- Chloro -6- cyclopropyl - N- (1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4- d ] pyrimidin -2 - amine

To a solution of 8-chloro-6-cyclopropyl-2-(methylsulfonyl)pyrido[3,4 -d ]pyrimidine (100 mg, 352 μmol) in anhydrous dimethylsulfoxide (1.8 mL) was charged 1-(methylsulfonyl)piperidin-4-amine (69.1 mg, 388 μmol), cesium fluoride (161 mg, 1.06 mmol) and N -ethyl- N -isopropylpropan-2-amine (137 mg, 184 μL, 1.06 mmol). The reaction vial was capped and stirred at 30 °C for 72 h. The crude mixture was diluted with water (50.0 mL) and extracted with dichloromethane (3 x 20.0 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (heptane/EtOAc, 1:1) to give the title compound (62.0 mg, 46% yield). LCMS (ESI) [M+H] ⁺ = 382.10 Step 2 : 6 -Cyclopropyl -8-(8,8- difluoro -2,6 -diazaspiro [3.4] octan -6- yl ) -N- (1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4- d ] pyrimidin -2- amine

To a solution of 8-chloro-6-cyclopropyl- N- (1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4- d ]pyrimidin-2-amine (22.0 mg, 58.0 μmol) in anhydrous dioxane (290 μL) were added tert-butyl-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate (17.0 mg, 69.0 μmol), sodium tert-butoxide (17.0 mg, 170 μmol) and [2'-(amino-κ N )[1,1'-biphenyl]-2-yl-κ C ][[2'-(diphenylphosphino)[1,1'-binaphthyl]-2-yl]diphenylphosphino-κ P ](methanesulfonato- κ O )-palladium (5.7 mg, 5.8 μmol). The reaction vial was capped and stirred at 100 °C for 16 h. The mixture was cooled to rt, diluted with ethyl acetate (30.0 mL) and water (20.0 mL), extracted (3 x 20.0 mL ethyl acetate), washed with brine, dried over anhydrous _MgSO4 , filtered and concentrated to dryness.

To the crude material was added trifluoroacetic acid (800 μL) at 0 °C. After 10 min, the reaction was allowed to warm to rt and stirring was continued until the reaction was complete as determined by LC-MS. Thereafter, the reaction was concentrated to dryness. The resulting solid was dissolved in dichloromethane (10 mL), neutralized with saturated aqueous NaHCO ₃ solution and extracted with dichloromethane (3×10.0 mL). The combined organic phases were concentrated to dryness and purified by preparative RP-HPLC to provide the title compound (14.0 mg, 48% yield). ¹ H NMR (DMSO-d ₆ , 499 MHz) δ 8.98 (s, 1H), 7.4-7.6 (m, 1H), 6.8-6.9 (m, 1H), 4.9-5.0 (m, 1H), 4.2-4.4 (m, 4H), 3.80 (d, 2H, J = 8.5 Hz), 3.60 (d, 2H, J = 12.3 Hz), 3.46 (d, 1H, J = 8.5 Hz), 2.8-3.0 (m, 5H), 2.04 (d, 2H, J = 12.3 Hz), 1.9-2.0 (m, 2H), 1.5-1.7 (m, 3H), 0.92 (m, 2H), 0.7-0.8 (m, 2H). LCMS (ESI) [M+H] ⁺ = 494.30 Example 62 : N-(1-( cyclopropylsulfonyl ) piperidin -4- yl )-8-(8,8- difluoro -2,6- diazaspiro [3.4] octan -6- yl )-6- methylpyrido [3,4-d] pyrimidin -2- amine Reaction Scheme Detailed Procedure Step 1 : 6-(2-((1-( cyclopropylsulfonyl ) piperidin -4- yl ) amino )-6 -methylpyrido [3,4-d] pyrimidin -8- yl )-8,8- difluoro -2,6- diazaspiro [3.4] octane -2- carboxylic acid tributyl ester

Pd-PEPPSI-iHeptCl 3-chloropyridine (255 mg, 0.26 mmol) was added to a mixture of 8-chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine (2 g, 5.23 mmol), tributyl 8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate (1.30 g, 5.23 mmol) and Cs ₂ CO ₃ (3.41 g, 10.47 mmol) in dioxane (30 mL) under nitrogen atmosphere. The resulting mixture was stirred at 100° C. overnight. The resulting mixture was filtered and the filter cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH, 3:97) to give tributyl 6-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate (2.8 g, 70.60% yield). LCMS (ESI-MS) m/z =594.3 [M+H] ⁺ . Step 2 : N-(1-( cyclopropylsulfonyl ) piperidin -4- yl )-8-(8,8- difluoro - 2,6- diazaspiro [3.4] octan -6- yl )-6 -methylpyrido [3,4-d] pyrimidin -2- amine

A solution of tributyl 6-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate (2.6 g, 4.37 mmol) in TFA (5 mL) and DCM (15 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated and the residue was purified by silica _gel column chromatography ( _CH2Cl2 /MeOH, 90:10) to give N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine (2.0686 g, 91.97% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.00 (s, 1H), 7.60 (s, 1H), 6.82 (s, 1H), 4.58-4.41 (m, 2H), 4.38-4.32 (m, 2H), 4.31-4.21 (m, 2H), 4.19-4.09 (m, 2H), 3.87 (s, 1H), 3.72-3.57 (m, 2H), 3.09-2.97 (m, 2H), 2.63-2.54 (m, 1H), 2.36 (s, 3H), 2.10-1.97 (m, 2H), 1.69-1.52 (m, 2H), 1.07-0.91 (m, 4H). LCMS (ESI-MS) m/z = 494.2 [M+H] ⁺ . Example 89 : 8-(8,8 -difluoro -2,6 -diazaspiro [3.4] octan -6- yl )-6- methyl -N-(1-((1- methyl -1H- pyrazol -4- yl ) sulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine Reaction Scheme Detailed Procedure Step 1 : 8,8 -Difluoro -6-(6- methyl -2-((1-((1- methyl -1H- pyrazol -4- yl ) sulfonyl ) piperidin -4- yl ) amino ) pyrido [3,4-d] pyrimidin -8- yl )-2,6 -diazaspiro [3.4] octane -2- carboxylic acid tributyl ester

A solution of 8-chloro-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (500 mg, 1.18 mmol), tributyl 8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate (293.83 mg, 1.18 mmol), Cs ₂ CO ₃ (1158.40 mg, 3.55 mmol) and Pd-PEPPSI-iHeptCl 3-chloropyridine (115.41 mg, 0.11 mmol) in dioxane (10 mL) was stirred at 100 °C overnight under nitrogen atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with EA (3×100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA, 1:1) to give 8,8-difluoro-6-(6-methyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tributyl ester (600 mg, 75.9% yield). LCMS (ESI-MS) m/z = 634.3 [M+H] ⁺ . Step 2 : 8-(8,8 -difluoro -2,6 -diazaspiro [3.4] octan -6- yl )-6- methyl -N-(1-((1- methyl -1H- pyrazol -4- yl ) sulfonyl ) piperidin -4 - yl ) pyrido [3,4-d] pyrimidin -2- amine A solution of tributyl 8,8-difluoro-6-(6-methyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (3 g, 4.73 mmol) in TFA (5 mL) and DCM (15 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica _gel column chromatography ( _CH2Cl2 /MeOH, 10:1) to give 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine TFA salt (2.3177 g, 91.7% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 2H), 8.98 (s, 1H), 8.34 (s, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 6.81 (s, 1H), 4.42 (s, 2H), 4.29 (s, 2H), 4.22 (d, J = 11.6 Hz, 2H), 4.09 (d, J = 11.5 Hz, 2H), 3.92 (s, 3H), 3.72 (s, 1H), 3.49 (d, J = 11.3 Hz, 2H), 2.53 (s, 2H), 2.35 (s, 3H), 2.0 2H), 1.69-1.57 (m, 2H). LCMS (ESI-MS) m/z = 534.2 [M+H] ⁺ . Example 97 : 8-(8,8-difluoro-2-methyl-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine

A mixture of 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (250 mg, 0.46 mmol) and formaldehyde (28.14 mg, 0.93 mmol) in MeOH (10 mL) was stirred at room temperature for 1 h. NaBH ₃ CN (117.77 mg, 1.87 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica _gel column chromatography ( _CH2Cl2 /MeOH, 10:1) to give 8-(8,8-difluoro-2-methyl-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (96.2 mg, 37.1% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.96 (s, 1H), 8.34 (s, 1H), 7.77 (d, J = 0.6 Hz, 1H), 7.53 (s, 1H), 6.76 (d, J = 0.9 Hz, 1H), 4.28 (s, 2H), 4.23 (s, 1H), 3.92 (s, 3H), 3.70 (s, 1H), 3.55 (d, J = 11.6 Hz, 2H), 3.39 (d, J = 7.8 Hz, 2H), 3.18 (s, 2H), 2.45 (d, J = 11.4 Hz, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 2.08 (s, 2H), 2.06-1.99 (m, 2H), 1.69-1.59 (m, 2H). LCMS (ESI-MS) m/z = 548.4 [M+H] ⁺ . Example 69 : (1-methyl-3-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)cyclobutyl)methanol Step 1 : 1- methyl - 3-(6- methyl -2-((1-( methylsulfonyl ) piperidin -4- yl ) amino ) pyrido [3,4-d] pyrimidin -8- yl ) cyclobutane -1 - carboxylic acid methyl ester

To an oven-dried 20 mL vial was charged methyl 3-hydroxy-1-methylcyclobutane-1-carboxylate (100 mg, 0.69 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (250 mg, 0.63 mmol). Under nitrogen, tert-butyl methyl ether (4 mL) was added and the reaction was stirred at room temperature for 5 minutes. A mixture of pyridine (50.16 mg, 0.63 mmol) in tert-butyl methyl ether (1 mL) was added and the mixture was stirred at room temperature for 10 minutes (Mixture A). To another oven-dried 40 mL vial was charged 8-chloro-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (141.04 mg, 0.39 mmol), NiBr ₂ (dtbbpy) (14.66 mg, 0.03 mmol), Ir(ppy) ₂ (dtbbpy)PF ₆ (5.43 mg, 0.006 mmol), o-phenylenediamine (9.65 mg, 0.02 mmol) and 1-azabicyclo[2.2.2]octane (77.1 mg, 0.69 mmol). DMA (5 mL) (Mixture B) was added under nitrogen. Mixture A was added to Mixture B under nitrogen atmosphere, and the resulting mixture was stirred and irradiated with a 450 nm LED lamp under a fan for 3 h. The residue was dissolved in water (20 mL) and extracted with EA (3×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA, 1:2) to give crude 1-methyl-3-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)cyclobutane-1-carboxylic acid methyl ester (90 mg). LCMS (ESI-MS) m/z = 448.2 [M+H] ⁺ . Step 2 : (1- methyl - 3- (6- methyl -2-((1-( methylsulfonyl ) piperidin -4- yl ) amino ) pyrido [ 3,4-d] pyrimidin -8- yl ) cyclobutyl ) methanol

DIBAL-H (47.67 mg, 0.336 mmol) was added to a solution of methyl 1-methyl-3-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)cyclobutane-1-carboxylate (50 mg, 0.112 mmol) in DCM (1 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h and quenched with water (20 mL) at 0 °C. The resulting mixture was extracted with DCM (3×20 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EA=100%) to give (1-methyl-3-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)cyclobutyl)methanol (1.1 mg, 2.33% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.95 (s, 1H), 7.22-7.11 (m, 1H), 5.31 (s, 1H), 4.65-4.51 (m, 1H), 4.41-4.26 (m, 1H), 4.18-3.99 (m, 1H), 3.87-3.68 (m, 3H), 3.52 (s, 1H), 3.11-2.93 (m, 2H), 2.93-2.78 (m, 4H), 2.76-2.68 (m, 2H), 2.44-2.16 (m, 5H), 1.87-1.60 (m, 5H), 1.19 (s, 1H). LCMS (ESI-MS) m/z = 420.2 [M+H] ⁺ . Example 70 : 6- Cyclopropyl -N-(1-( methylsulfonyl ) piperidin -4- yl )-8-(5- oxa -8- azaspiro [3.5] nonan -2- yl ) pyrido [3,4-d] pyrimidin -2- amine Reaction Scheme Detailed Procedure Step 1 : 8- Chloro - 6- cyclopropyl - N- (1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2 - amine

DIEA (137 mg, 1.05 mmol) was added to a mixture of 8-chloro-6-cyclopropyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (100 mg, 0.35 mmol), 1-(methylsulfonyl)piperidin-4-amine (62.8 mg, 0.35 mmol) and CsF (161 mg, 1.05 mmol) in DMSO (2 mL) at room temperature. The resulting mixture was stirred at 80 °C overnight. The residue was dissolved in water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA, 1:2) to give crude 8-chloro-6-cyclopropyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (80 mg). LCMS (ESI-MS) m/z = 382.2 [M+H] ⁺ . Step 2 : 2-(6- cyclopropyl - 2-((1-( methylsulfonyl ) piperidin -4- yl ) amino ) pyrido [3,4-d] pyrimidin -8- yl )-5- oxa - 8 - azaspiro [ 3.5] nonane - 8- carboxylic acid tributyl ester

To an oven-dried 20 mL vial was charged tert-butyl 2-hydroxy-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate (55.7 mg, 0.229 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (82.8 mg, 0.21 mmol). Under nitrogen, tert-butyl methyl ether (4 mL) was added and the reaction was stirred at room temperature for 5 minutes. A mixture of pyridine (16.57 mg, 0.21 mmol) in tert-butyl methyl ether (1 mL) was added and the mixture was stirred at room temperature for 10 minutes (Mixture A). To another oven-dried 40 mL vial was charged 8-chloro-6-cyclopropyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (50 mg, 0.13 mmol), NiBr ₂ (dtbbpy) (4.88 mg, 0.01 mmol), Ir(ppy) ₂ (dtbbpy)PF ₆ (1.79 mg, 0.002 mmol), 1-azabicyclo[2.2.2]octane (25.89 mg, 0.23 mmol) and quinidine cyclopentane (25.48 mg, 0.229 mmol). DMA (5 mL) (Mixture B) was added under nitrogen. Mixture A was added to Mixture B under nitrogen atmosphere, and the resulting mixture was stirred and irradiated with a 450 nm LED lamp under a fan for 3 h. The residue was dissolved in water (20 mL) and extracted with EA (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA, 1:2) to give crude 2-(6-cyclopropyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylic acid tributyl ester (50 mg). LCMS (ESI-MS) m/z = 573.2 [M+H] ⁺ . Step 3 : 6- cyclopropyl - N- (1-( methylsulfonyl ) piperidin -4- yl ) -8-(5- oxa - 8 - azaspiro [3.5] nonan - 2 - yl ) pyrido [3,4-d] pyrimidin -2- amine

TFA (0.1 mL) was added to a solution of tributyl 2-(6-cyclopropyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate (50 mg, 0.087 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative RP-HPLC to give 6-cyclopropyl-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(5-oxa-8-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine (1.0 mg, 2.30% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.93 (s, 1H), 7.16 (s, 1H), 5.30-5.20 (m, 1H), 4.12-3.91 (m, 2H), 3.87-3.67 (m, 4H), 3.19-2.98 (m, 4H), 2.96-2.80 (m, 5H), 2.61-2.49 (m, 4H), 2.34-2.20 (m, 3H), 2.17-2.00 (m, 1H), 1.83-1.65 (m, 2H), 1.15-1.05 (m, 2H), 1.02-0.93 (m, 2H). LCMS (ESI-MS) m/z = 473.2 [M+H] ⁺ . Example 93 : 1-( Difluoromethyl )-3-(6- methyl -2-((1-( methylsulfonyl ) piperidin -4- yl ) amino ) pyrido [3,4-d] pyrimidin -8- yl ) cyclobutan -1- ol Reaction Scheme Detailed Procedure Step 1 : 1- ( Difluoromethyl )-3-(6- methyl - 2- ( (1-( methylsulfonyl ) piperidin - 4- yl ) amino ) pyrido [ 3,4-d] pyrimidin -8 -yl ) cyclobutylbenzoate

To an oven-dried 20 mL vial was charged 1-(difluoromethyl)-3-hydroxycyclobutylbenzoate (106 mg, 0.44 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (158 mg, 0.40 mmol). Under nitrogen, tert-butyl methyl ether (4 mL) was added and the reaction was stirred at room temperature for 5 minutes. A mixture of pyridine (31.6 mg, 0.40 mmol) in tert-butyl methyl ether (1 mL) was added and the mixture was stirred at room temperature for 10 minutes (Mixture A). To another dried 40 mL vial was charged 8-bromo-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (100 mg, 0.25 mmol), Ir(ppy) ₂ (dtbbpy) _PF6 (3.43 mg, 0.004 mmol), _NiBr2 (dtbbpy) (9.78 mg, 0.02 mmol), o-phenylenediamine (8.27 mg, 0.056 mmol) and 1-azabicyclo[2.2.2]octane (48.6 mg, 0.44 mmol). DMA (5 mL) (Mixture B) was added under nitrogen. Mixture A was added to Mixture B under nitrogen atmosphere, and the resulting mixture was stirred and irradiated with a 450 nm LED lamp under a fan for 3 h. The residue was dissolved in water (20 mL) and extracted with EA (3×20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA, 1:2) to give crude 1-(difluoromethyl)-3-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)cyclobutylbenzoate (50 mg, 36.68% yield). LCMS (ESI-MS) m/z = 546.2 [M+H] ⁺ . Step 2 : 1-( difluoromethyl )-3-(6- methyl -2-((1-( methylsulfonyl ) piperidin -4- yl ) amino ) pyrido [ 3,4-d] pyrimidin -8- yl ) cyclobutan - 1 - ol

LiOH (10.9 mg, 0.46 mmol) was added to a solution of 1-(difluoromethyl)-3-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)cyclobutylbenzoate (50 mg, 0.09 mmol) in THF (3 mL) and H ₂ O (1 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with EA (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to give 1-(difluoromethyl)-3-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)cyclobutan-1-ol (5.8 mg, 13.36%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.16 (s, 1H), 7.70 (s, 1H), 7.37 (s, 1H), 6.06-5.85 (m, 2H), 4.08-3.86 (m, 2H), 3.60-3.50 (m, 2H), 2.96-2.83 (m, 5H), 2.72-2.62 (m, 2H), 2.59-2.52 (m, 4H), 2.14-2.01 (m, 3H), 1.67-1.55 (m, 2H). LCMS (ESI-MS) m/z = 442.1[M+H] ⁺ . Example 99 : 8-(8,8- difluoro -6- azaspiro [3.4] octan -2- yl )-6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine Reaction Scheme Step 1 : 8,8 -difluoro -2-(6- methyl -2-((1-( methylsulfonyl ) piperidin -4- yl ) amino ) pyrido [3,4-d] pyrimidin -8- yl ) -6- azaspiro [ 3.4] octane -6- carboxylic acid tributyl ester

To an oven-dried 20 mL vial was charged tert-butyl 8,8-difluoro-2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (207 mg, 0.78 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (284 mg, 0.72 mmol). Under nitrogen, tert-butyl methyl ether (4 mL) was added and the reaction was stirred at room temperature for 5 minutes. A mixture of pyridine (56.9 mg, 0.72 mmol) in tert-butyl methyl ether (1 mL) was added and the mixture was stirred at room temperature for 10 minutes (Mixture A). To another dried 40 mL vial was charged 8-bromo-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (180 mg, 0.45 mmol), Ir(ppy) ₂ (dtbbpy) _PF6 (6.16 mg, 0.007 mmol), _NiBr2 (dtbbpy) (16.42 mg, 0.034 mmol), o-phenylenediamine (26.46 mg, 0.18 mmol) and 1-azabicyclo[2.2.2]octane (87.49 mg, 0.78 mmol). DMA (5 mL) (Mixture B) was added under nitrogen. Mixture A was added to Mixture B under nitrogen atmosphere, and the resulting mixture was stirred and irradiated with a 450 nm LED lamp under a fan for 3 h. The residue was dissolved in water (20 mL) and extracted with EA (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA, 1:2) to give tributyl 8,8-difluoro-2-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-6-azaspiro[3.4]octane-6-carboxylate (20 mg, 7.85% yield). LCMS (ESI-MS) m/z = 567.2 [M+H] ⁺ . Step 2 : 8-(8,8 -difluoro - 6- azaspiro [3.4] octan -2- yl )-6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin - 2 - amine

TFA (0.23 mL) was added to a solution of tributyl 8,8-difluoro-2-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-6-azaspiro[3.4]octane-6-carboxylate (20 mg, 0.035 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH, 10:1) to give 8-(8,8-difluoro-6-azaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (1.0 mg, 5.65% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.04 (s, 1H), 7.32 (s, 1H), 4.10-3.99 (m, 1H), 3.80-3.70 (m, 2H), 3.24-3.13 (m, 2H), 3.09-2.96 (m, 2H), 2.91-2.88 (m, 4H), 2.84-2.77 (m, 2H), 2.61 (s, 3H), 2.52-2.44 (m, 1H), 2.36-2.15 (m, 4H), 1.84-1.66 (m, 2H), 0.94-0.83 (m, 2H). LCMS (ESI-MS) m/z = 467.3 [M+H] ⁺ . Example 100 : 8-(8-( Difluoromethyl )-2,6 -diazaspiro [3.4] octan -2- yl )-6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine Reaction Scheme Detailed Procedure Step 1 : 8-( Difluoromethyl )-2-(6- methyl -2-((1-( methylsulfonyl ) piperidin -4- yl ) amino ) pyrido [3,4-d] pyrimidin -8- yl )-2,6 -diazaspiro [3.4] octane -6- carboxylic acid benzyl ester

Pd-PEPPSI-iHeptCl 3-chloropyridine (31.55 mg, 0.03 mmol) was added to a mixture of 8-(difluoromethyl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid benzyl ester (96 mg, 0.32 mmol), 8-bromo-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (129.69 mg, 0.32 mmol) and Cs ₂ CO ₃ (211.12 mg, 0.64 mmol) in dioxane (3 mL) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C overnight under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH, 10:1) to give 8-(difluoromethyl)-2-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid benzyl ester (150 mg, 58.43% yield). LCMS (ESI-MS) m/z =616.3 [M+H] ⁺ . Step 2 : 8-(8-( difluoromethyl )-2,6 -diazaspiro [3.4] octan -2- yl )-6- methyl -N-(1-( methylsulfonyl ) piperidin -4 -yl ) pyrido [3,4-d] pyrimidin -2- amine

Pd/C (116.67 mg, 0.11 mmol, 10%/carbon) was added to a solution of 8-(difluoromethyl)-2-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid benzyl ester (135 mg, 0.21 mmol) in MeOH (5 mL) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative _TLC ( _CH2Cl2 /MeOH, 10:1). The product was further purified by preparative RP-HPLC to give 8-(8-(difluoromethyl)-2,6-diazaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (14.6 mg, 13.25% yield). ¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.04-8.68 (m, 1H), 7.45-7.11 (m, 1H), 6.64 (d, J = 4.1 Hz, 1H), 6.03 (t, J = 55.8 Hz, 1H), 5.32-5.06 (m, 1H), 4.92-4.68 (m, 1H), 4.34 (s, 3H), 4.10-3.91 (m, 1H), 3.89-3.73 (m, 2H), 3.51-3.07 (m, 4H), 3.05-2.92 (m, 2H), 2.91-2.78 (m, 3H), 2.73-2.56 (m, 1H), 2.56-2.35 (m, 3H), 2.22 (s, 2H), 1.83-1.65 (m, 2H). LCMS (ESI-MS) m/z = 482.4 [M+H] ⁺ . Examples 103 and 104 : (R)-8-(8- fluoro -6- methyl -2,6- diazaspiro [3.4] octan -2- yl )-6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine and (S)-8-(8- fluoro -6- methyl -2,6- diazaspiro [3.4] octan -2- yl )-6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine Reaction Scheme Detailed Procedure Step 1 : 8- Fluoro -2-(6- methyl -2-((1-( methylsulfonyl ) piperidin -4- yl ) amino ) pyrido [3,4-d] pyrimidin -8- yl )-2,6 -diazaspiro [3.4] octane -6- carboxylic acid tributyl ester

To a solution of 8-bromo-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (180 mg, 0.45 mmol) in dioxane (1 mL, 11.80 mmol) under nitrogen atmosphere, tributyl 8-fluoro-2,6-diazaspiro[3.4]octane-6-carboxylate (103.55 mg, 0.45 mmol), Pd-PEPPSI-iHeptCl 3-chloropyridine (43.79 mg, 0.04 mmol) and Cs ₂ CO ₃ (293.02 mg, 0.90 mmol) were added. The resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. The mixture was filtered and the filter cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 1:9) to give 8-fluoro-2-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid tributyl ester (180 mg, 58.26% yield). LCMS (ESI-MS) m/z =550.2 [M+H] ⁺ . Step 2 : 8-(8- fluoro -2,6- diazaspiro [3.4] octan -2- yl )-6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine

A solution of tributyl 8-fluoro-2-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (180 mg, 0.327 mmol) in TFA (0.6 mL) and DCM (2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give crude 8-(8-fluoro-2,6-diazaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (145 mg, 78.80% yield). LCMS (ESI-MS) m/z = 450.2 [M+H] ⁺ . Step 3 : 8-(8- Fluoro -6- methyl -2,6- diazaspiro [3.4] octan -2- yl )-6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine

A mixture of 8-(8-fluoro-2,6-diazaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (135 mg, 0.300 mmol) and HCHO (10.82 mg, 0.36 mmol) in DCE (1.5 mL) was stirred at room temperature overnight. STAB (95.47 mg, 0.45 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was purified by silica gel column chromatography (DCM/MeOH, 10:1) to give racemic 8-(8-fluoro-6-methyl-2,6-diazaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (10.2 mg, 7.09%). LCMS (ESI-MS) m/z = 464.2 [M+H] ⁺ . Step 4 : (R)-8-(8- fluoro -6- methyl -2,6 - diazaspiro [3.4] octan - 2- yl )-6- methyl -N-(1-( methylsulfonyl ) piperidin - 4- yl ) pyrido [ 3,4-d] pyrimidin -2- amine and (S)-8-(8- fluoro -6- methyl -2,6- diazaspiro [3.4] octan -2- yl )-6- methyl -N-(1-( methylsulfonyl ) piperidin -4- yl ) pyrido [3,4-d] pyrimidin -2- amine

Racemic 8-(8-fluoro-6-methyl-2,6-diazaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine was separated by preparative chiral HPLC using the following conditions: Column: chiral cellulose SB, 4.6*100 mm, 3 μm. Mobile phase: Hex (0.1% DEA)/(EtOH/DCM, 1:1), 75:25.

The desired fractions were combined and lyophilized to obtain the title product as a single mirror image isomer. First elution peak : 17.4 mg, 99.8% ee, 7.09% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (s, 1H), 7.45-7.41 (m, 1H), 6.70 (s, 1H), 5.30-5.15 (m, 1H), 4.54-4.17 (m, 3H), 3.82 (s, 1H), 3.57-3.54 (m, 2H), 2.96-2.88 (m, 5H),2.84-2.82 (m, 2H), 2.67-2.50 (m, 3H), 2.49-2.28 (m, 6H), 2.12-1.95 (m, 2H), 1.71-1.52 (m, 2H). LCMS (ESI-MS) m/z = 464.2 [M+H] ⁺ . Second elution peak : 14.4 mg, 99.6% ee, 9.85% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (s, 1H), 7.49-7.43 (m, 1H), 6.70 (s, 1H), 5.30-5.15 (m, 1H), 4.53-4.13 (m, 3H), 3.82 (s, 1H), 3.58-3.56 (m, 2H), 3.01-2.82 (m, 7H),2.67-2.63 (m, 3H), 2.50-2.28 (m, 6H), 2.02-1.99 (m, 2H), 1.71-1.59 (m, 2H). LCMS (ESI-MS) m/z = 464.2 [M+H] ⁺ .

In some embodiments, the compounds of the present invention are in Table 1 below. Table 1 Compound No. Structure Name Mass spectrum M+H/1 1 8-(4-cyclopropylpiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 432.2 2 8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 453 3 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 439.2 4 8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-N-(4-(4-methylpiperidin-1-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine 466.2 5 3-Cyclopropyl-1-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyrrolidine-3-carbonitrile 442.2 6 8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-2-amine 493 7 N-(1-(Methylsulfonyl)piperidin-4-yl)-8-(8-oxa-2-azaspiro[4.5]dec-2-yl)pyrido[3,4-d]pyrimidin-2-amine 447.2 8 8-(6-cyclopropyl-2,6-diazaspiro[3.3]hept-2-yl) -N- (1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 444.2 9 N- (4-(4-methylpiperidin-1-yl)phenyl)-8-(7-(methylsulfonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine 523.3 10 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrroline-2-yl)pyrido[3,4-d]pyrimidin-2-amine 413.1 11 8-(8,8-difluoro-2-(methyl-d3)-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 551.3 12 8-(8,8-difluoro-2-(methyl-d3)-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 485.3 13 N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-8-(8,8-difluoro-2-(methyl-d3)-2,6-diazaspiro[3.4]octan-6-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine 511.3 14 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(1-(methylsulfonyl)azacyclobut-3-yl)pyrido[3,4-d]pyrimidin-2-amine 411.1 15 N-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)-8-(7-(methylsulfonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine 444.1 16 (3aR,8bR)-2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2,3,3a,8b-tetrahydro-1H-benzo[4,5]thieno[2,3-c]pyrrole 4,4-dioxide 515 17 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)pyrido[3,4-d]pyrimidin-2-amine 373.1 18 N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)-8-(8-oxa-2-azaspiro[4.5]dec-2-yl)pyrido[3,4-d]pyrimidin-2-amine 487.2 19 8-(4'-Fluorospiro[cyclopentane-1,3'-indolin]-1'-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 497.1 20 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine 441.2 twenty one 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-2-amine 479.2 twenty two 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(2-methylisoindolin-5-yl)pyrido[3,4-d]pyrimidin-2-amine 409.2 twenty three N-(2-methylisoindolin-5-yl)-8-(7-(methylsulfonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine 480.2 twenty four 6-(2-((2-methylisoindolin-5-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide 423.1 25 N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-6-methyl-8-(2,6-diazaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine 458.3 26 6-Methyl-N-(1-(2-methyl-2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-8-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)pyrido[3,4-d]pyrimidin-2-amine 510.1 27 6-Methyl-8-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(2-(methylsulfonyl)isoindol-5-yl)pyrido[3,4-d]pyrimidin-2-amine 466.2 28 3-Cyclopropyl-1-(6-methyl-2-((4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyrrolidine-3-carbonitrile 481.3 29 6-methyl-8-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(2-(1-(methylsulfonyl)azepinecyclobut-3-yl)isoindolin-5-yl)pyrido[3,4-d]pyrimidin-2-amine 521.3 30 6-(6-methyl-2-((4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide 492.1 31 2-(3-(4-((6-methyl-8-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azepanobutyl-1-yl)acetonitrile 431.2 32 N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-6-methyl-8-(2,6-diazaspiro[3.3]hept-2-yl)pyrido[3,4-d]pyrimidin-2-amine 444.2 33 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-6-methyl-N-(1-(2-methyl-2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine 467.2 34 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-6-methyl-N-(4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine 478.2 35 6-Methyl-N-(4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)phenyl)-8-(8-oxa-2-azaspiro[4.5]dec-2-yl)pyrido[3,4-d]pyrimidin-2-amine 486.2 36 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(1-((1-(dimethylamino)cyclopropyl)methyl)-1H-pyrazol-4-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine 455.1 37 N-(6-Fluoro-2-(methylsulfonyl)isoindolin-5-yl)-6-methyl-8-(2,6-diazaspiro[3.3]hept-2-yl)pyrido[3,4-d]pyrimidin-2-amine 470.2 38 3-Cyclopropyl-1-(2-((1-((1-(dimethylamino)cyclopropyl)methyl)-1H-pyrazol-4-yl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)pyrrolidine-3-carbonitrile 458.2 39 N-(6-fluoro-2-(methylsulfonyl)isoindolin-5-yl)-6-methyl-8-(2,6-diazaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine 484.2 40 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-((1r,4r)-4-((dimethylamino)methyl)cyclohexyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine 431.2 41 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-6-methyl- N -(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4- d ]pyrimidin-2-amine 453.3 42 8-(6-cyclopropyl-2,6-diazaspiro[3.3]hept-2-yl)-6-methyl- N -(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4- d ]pyrimidin-2-amine 458.3 43 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-6-methyl-N-(2-methyl-2-azabicyclo[2.2.1]hept-5-yl)pyrido[3,4-d]pyrimidin-2-amine 401.2 44 8-(6-cyclopropyl-2,6-diazaspiro[3.3]hept-2-yl)-6-methyl- N- (2-methylisoindolin-5-yl)pyrido[3,4 -d ]pyrimidin-2-amine 428.3 45 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-((1s,4s)-4-((dimethylamino)methyl)cyclohexyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine 431.2 46 1-(Cyclopropanesulfonyl)-N-(8-{2,6-diazaspiro[3.4]octan-2-yl}-6-(difluoromethyl)pyrido[3,4-d]pyrimidin-2-yl)piperidin-4-amine 494.3 47 N-(2-cyclopropylisoindolin-5-yl)-6-methyl-8-(2,6-diazaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine 428.3 48 8-(6-cyclopropyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine 484.2 49 N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-6-methyl-8-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine 472.2 50 N- (2-cyclopropylisoindolin-5-yl)-6-(difluoromethyl)-8-(2,6-diazaspiro[3.4]octan-2-yl)pyrido[3,4- d ]pyrimidin-2-amine 464.2 51 N-(1-((Cyclopentylmethyl)sulfonyl)piperidin-4-yl)-6-methyl-8-(2,6-diazaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine 500.3 52 8-(1,1-difluoro-6-azaspiro[3.4]octan-6-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 467.3 53 8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 467.3 54 6-Methyl-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(5-azaspiro[2.4]hept-5-yl)pyrido[3,4-d]pyrimidin-2-amine 417.3 55 N- (1-((Cyclobutylmethyl)sulfonyl)piperidin-4-yl)-6-(difluoromethyl)-8-(2,6-diazaspiro[3.4]octan-2-yl)pyrido[3,4- d ]pyrimidin-2-amine 522.3 56 3-Cyclopropyl-1-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)azepinecyclobutan-3-ol 459.2 57 8-(3-cyclopropoxyazidocyclobutan-1-yl)-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine 459.3 58 N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-8-(3-(difluoromethoxy)pyrrolidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine 483.3 59 6-Methyl-8-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)-N-(1-((1-methylcyclopropyl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 486.3 60 6-Cyclopropyl-8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl) -N- (1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4- d ]pyrimidin-2-amine 494.3 61 N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-8-(5,5-difluoro-2,7-diazaspiro[3.5]nonan-2-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine 508.3 62 N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine 494.2 63 1-Methyl-3-(6-methyl-2-((1-((1-methylcyclopropyl)sulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)cyclobutan-1-ol 446.2 64 N- (1-((Cyclobutylmethyl)sulfonyl)piperidin-4-yl)-6-cyclopropyl-8-(6-(2-methoxyethyl)-2,6-diazaspiro[3.3]hept-2-yl)pyrido[3,4- d ]pyrimidin-2-amine 556.3 65 8-(9,9-difluoro-2,6-diazaspiro[3.5]nonan-2-yl)-6-(difluoromethyl)- N -(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4- d ]pyrimidin-2-amine 518.2 66 2-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6-methylpyrido[3,4- d ]pyrimidin-8-yl)-2-azaspiro[3.3]heptan-6-ol 459.2 67 8-(8,8-Difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl- N -(1-((2-(1-methylcyclopropyl)ethyl)sulfonyl)piperidin-4-yl)pyrido[3,4- d ]pyrimidin-2-amine 536.3 68 1-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6-methylpyrido[3,4- d ]pyrimidin-8-yl)-3-(2-fluoroethyl)azinecyclobutane-3-carbonitrile 474.3 69 (1-methyl-3-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)cyclobutyl)methanol 421.2 70 6-Cyclopropyl-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(5-oxa-8-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine 473.2 71 N- (1-(Cyclopropylsulfonyl)piperidin-4-yl)-8-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-6-methylpyrido[3,4- d ]pyrimidin-2-amine 473.3 72 N- (1-(Cyclopropylsulfonyl)piperidin-4-yl)-8-(3-fluoro-[1,3'-azidocyclobutane]-1'-yl)-6-methylpyrido[3,4- d ]pyrimidin-2-amine 476.2 73 2-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4- d ]pyrimidin-8-yl)-2-azaspiro[3.3]heptan-6-ol 433.2 74 N- (1-(Cyclopropylsulfonyl)piperidin-4-yl)-6-methyl-8-(3-((methylsulfonyl)methyl)azepanobutyl-1-yl)pyrido[3,4 -d ]pyrimidin-2-amine 495.2 75 6-Cyclopropyl-8-(6-methoxy-2-azaspiro[3.3]hept-2-yl) -N- (1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4 -d ]pyrimidin-2-amine 473.3 76 8-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-6-methyl- N -(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4- d ]pyrimidin-2-amine 447.2 77 2-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4- d ]pyrimidin-8-yl)-2,5-diazaspiro[3.4]octan-6-one 446.2 78 2-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6-methylpyrido[3,4- d ]pyrimidin-8-yl)-6-methyl-2-azaspiro[3.3]heptan-6-ol 473.2 79 6-Methyl-2-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4- d ]pyrimidin-8-yl)-2-azaspiro[3.3]heptan-6-ol 447.2 80 N- (1-((Cyclobutylmethyl)sulfonyl)piperidin-4-yl)-6-cyclopropyl-8-(2-(2-methoxyethyl)-2-azaspiro[3.3]hept-6-yl)pyrido[3,4- d ]pyrimidin-2-amine 555.4 81 2-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4- d ]pyrimidin-8-yl)-2,6-diazaspiro[3.4]octan-7-one 446.2 82 2-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4- d ]pyrimidin-8-yl)-2,6-diazaspiro[3.5]nonan-7-one 460.2 83 3-Cyclopropyl-1-(6-methyl-2-((4-((methylsulfonyl)methyl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)azepinecyclobutan-3-ol 440.1 84 6-methyl-8-(8-methyl-5-oxa-8-azaspiro[3.5]nonan-2-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 461.3 85 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 468.3 86 3-Cyclopropyl-1-(2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)azepinecyclobutan-3-ol 372.2 87 8-(5,5-difluoro-2,7-diazaspiro[3.5]nonan-2-yl)-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 548.3 88 1-Cyclopropyl-3-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)cyclobutan-1-ol 432.2 89 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 534.2 90 8-(5,5-difluoro-2,7-diazaspiro[3.5]nonan-2-yl)-6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 518.2 91 3-(Difluoromethyl)-1-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)azepinecyclobutan-3-ol 443.1 92 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 468.1 93 1-(Difluoromethyl)-3-(6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)cyclobutan-1-ol 442.1 94 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 534 95 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-N-(1-(ethylsulfonyl)piperidin-4-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine 482 96 8-(8,8-difluoro-2-methyl-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 482.2 97 8-(8,8-difluoro-2-methyl-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 548.4 98 8-(8-Fluoro-2,6-diazaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 450.1 99 8-(8,8-difluoro-6-azaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 467.3 100 8-(8-(Difluoromethyl)-2,6-diazaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 482.4 101 8-(8,8-difluoro-6-methyl-2,6-diazaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 482.3 102 N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-8-(8,8-difluoro-2-methyl-2,6-diazaspiro[3.4]octan-6-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine 508.2 103 (R)-8-(8-Fluoro-6-methyl-2,6-diazaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 464.2 104 (S)-8-(8-Fluoro-6-methyl-2,6-diazaspiro[3.4]octan-2-yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 464.2

The NMR of the compounds of Table 1 is provided in Table 1B below. Table 1B Compound No. ^1H NMR (ppm) 1 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 9.09 (s, 1H), 7.95-7.80 (m,1H), 7.79-7.32 (m, 1H), 7.12-6.96 (m, 1H), 4.00-3.71 (m, 5H), 3.70-3.50 (m, 2H), 3.02-2.81 (m, 5H), 2.80-2.61 (m, 4H), 2.15-1.92 (m, 2H), 1.78-1.55 (m, 3H), 0.55-0.41 (m, 2H), 0.40-0.25 (m, 2H). 2 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.73 (d, J = 5.6 Hz, 1H), 7.52 (s, 1H), 6.81 (d, J = 5.2 Hz, 1H), 4.10 (s, 2H), 3.89 (s, 3H), 3.59 (d, J = 12.4 Hz, 2H), 2.93-2.86 (m, 5H), 2.75-2.56 (m, 4H), 2.13-1.96 (m, 4H), 1.69-1.56 (m, 2H). 3 ¹ H NMR (300 MHz, DMSO- d ₆ ) δ(ppm) 9.03 (s, 1H), 7.76 (d, J=6.0Hz, 1H), 7.57-7.51 (m, 1H), 6.87 (d, J=6.0Hz, 1H), 4.45-4.27 (m, 1H), 4.11-3.98 (m, 3H), 3.91-3.70 (m, 1H), 3.59-3.55 (m, 2H), 2.98-2.80 (m, 5H), 2.25-2.07 (m, 1H), 2.16-1.99 (m, 3H), 1.73-1.60 (m, 4H). 4 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 9.48 (s, 1H), 9.10 (s,1H), 7.90 (d, j=5.6 Hz, 1H), 7.51 (d, j=9.2 Hz, 2H), 7.01-6.82 (m, 3H), 4.12-3.95 (m, 2H), 3.92-3.72 (m, 2H), 3.20-3.01 (m, 4H), 2.70-2.55 (m, 4H), 2.50-2.38 (m, 4H), 2.30-2.15 (m, 3H), 2.10-1.92 (m, 2H). 5 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 9.04 (s, 1H), 7.77 (d, j=5.2 Hz, 1H), 7.62 (s, 1H), 6.90 (d, j=5.6 Hz, 1H), 4.75-4.41 (m, 1H), 4.20-3.96 (m, 3H), 3.92-3.72 (m, 1H), 3.71-3.55 (m, 2H), 2.98-2.80 (m, 5H), 2.45-2.38 (m, 1H), 2.25-2.16 (m, 1H), 2.08-1.99 (m, 2H), 1.70-1.51 (m, 2H), 1.36-1.25 (m, 1H), 0.70-0.55 (m, 2H), 0.54-0.41 (m, 2H). 6 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.13 (s, 1H), 7.94-7.62 (m, 3H), 7.14-6.97 (m, 2H), 4.39 (s, 4H), 4.12-4.18 (m, 6H), 3.98-3.92 (m, 2H), 3.27-3.25 (m, 2H), 2.67-2.61 (m, 4H), 2.16-2.13 (m, 2H), 1.42-1.34 (m, 1H), 1.31-1.23 (m, 3H). 7 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm) 8.98 (s, 1H), 7.72 (d, J=7.2 Hz, 1H), 7.46 (s, 1H), 6.78 (d, J=7.2 Hz, 1H), 4.00-3.80 (m, 5H), 3.75-3.52 (m, 6H), 2.95-2.86 (m, 5H), 2.12-2.00 (m, 2H), 1.98-1.80 (m, 2H), 1.70-1.50 (m, 6H). 8 ¹ H NMR (300 MHz, CDCl ₃ ) δ(ppm) 8.97-8.69 (m, 1H), 7.97-7.75 (m, 1H), 6.84-6.66 (m, 1H), 5.35-5.13 (m, 1H), 4.71-4.31 (m, 4H), 4.15-3.88 (m, 1H), 3.82-3.68(m, 2H), 3.65-3.44 (m, 4H), 3.19-2.99 (m, 2H), 2.96-2.75 (m, 3H), 2.33-2.15 (m, 2H), 2.14-1.85 (m, 3H), 0.56-0.30 (m, 4H). 9 ¹ H NMR (300 MHz, CDCl ₃ ) δ(ppm) 8.94 (d, J=3.8 Hz, 1H), 7.91 (d, J=5.5 Hz, 1H), 7.45-7.36 (m, 2H), 7.12 (s, 1H), 6.97 (dd, J=9.5, 2.8 Hz, 2H), 6.78 (d, J=5.5 Hz, 1H), 4.11-3.95 (m, 3H), 3.89 (d, J=11.7 Hz, 1H), 3.52 (dt, J= 9.9, 6.8 Hz, 1H), 3.45-3.30 (m, 3H), 3.23 (d, J=5.7 Hz, 4H), 2.81 (d, 3H), 2.69-2.57 (m, 4H), 2.39 (d, J=5.6 Hz, 3H), 2.00 (td, J=9.2, 7.5, 3.8 Hz, 4H). 10 ¹ H-NMR (400 MHz, chloroform- d ) δ (ppm) 9.18-8.91 (m, 1H), 8.08-7.80 (m, 2H), 6.90-6.69 (m, 1H), 6.44-6.24 (m, 1H), 4.48-4.32 (m, 1H), 4.28-3.99 (m, 5H), 3.75-3.55 (m, 2H), 2.94 (s, 2H), 2.63-2.45 (m, 3H), 2.30 (s, 1H), 2.05 (s, 1H), 1.52-1.36 (m, 2H). 11 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.96 (s, 1H), 8.34 (s, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 6.76 (s, 1H), 4.33-4.24 (m, 2H), 4.23-4.15 (m, 1H), 3.92 (s, 3H), 3.70 (m, 1H), 3.60-3.50 (m, 2H), 3.31-3.25 (m, 2H), 3.18-2.99 (m, 2H), 2.49-2.40 (m, 3H), 2.33 (s, 3H), 2.08-1.97 (m, 2H), 1.70-1.54 (m, 2H). 12 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.98 (s, 1H), 7.54 (s, 1H), 6.78 (s, 1H), 4.40-4.22 (m, 4H), 3.90-3.79 (m, 1H), 3.61 (d, J = 11.6 Hz, 3H), 3.26-3.15 (m, 3H), 2.97-2.84 (m, 5H), 2.34 (s, 3H), 2.13-1.98 (m, 2H), 1.69-1.55 (m, 2H) 13 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.98 (s, 1H), 7.54 (s, 1H), 6.78 (s, 1H), 4.40-4.19 (m, 4H), 3.90-3.79 (m, 1H), 3.72-3.63 (m, 2H), 3.38-3.35 (m, 1H), 3.20 (d, J = 7.6 Hz, 2H), 3.00 (t, J = 11.6 Hz, 2H), 2.70-2.56 (m, 2H), 2.34 (s, 3H), 2.09-2.00 (m, 2H), 1.67-1.51 (m, 2H), 1.03-0.90 (m, 4H) 14 ¹ H NMR (400 MHz, CDCL ₃ ) δ (ppm) 8.92 (s, 1H), 7.92-7.90 (m, 1H), 6.81-6.79 (m, 1H), 5.70 (s, 1H), 4.82-4.75 (m, 1H), 4.32-4.08 (m, 6H), 3.96-3.91 (m, 2H), 2.93 (s, 3H), 2.36-2.27 (m, 1H), 2.17-2.01 (m, 1H), 1.65-1.60 (m, 2H). 15 ¹ H-NMR (400 MHz, CHLOROFORM- d ) δ (ppm) 8.83 (s, 1H), 7.87 (d, J = 5.5 Hz, 1H), 6.74 (d, J = 5.5 Hz, 1H), 5.35 (s, 1H), 4.31 (s, 2H), 4.16-3.96 (m, 2H), 3.62-3.44 (m, 2H), 3.41 (s, 2H), 3.22-3.06 (m, 3H), 2.90 (s, 3H), 2.53-2.46 (m, 2H), 2.37 (s, 3H), 2.13-2.01 (m, 4H), 1.64 (d, J = 2.6 Hz, 2H). 16 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.85-7.71 (m, 4H), 7.69-7.53 (m, 2H), 6.96 (d, J = 5.6 Hz, 1H), 5.22-5.02 (m, 1H), 4.53-4.36 (m, 3H), 4.15-3.96 (m, 3H), 3.65-3.50 (m, 2H), 3.03-2.86 (m, 5H), 2.07-1.93 (m, 2H), 1.70-1.51 (m, 2H). 17 ¹ H-NMR (400 MHz, chloroform- d ) δ (ppm) 8.93-8.77 (m, 1H), 7.97-7.80 (m, 1H), 6.86-6.67 (m, 1H), 5.49-5.30 (m, 1H), 4.51-4.11 (m, 4H), 3.25-3.01 (m, 3H), 2.55-2.05 (m, 8H), 1.54-1.23 (m, 3H). 18 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.83 (d, J = 5.2 Hz, 1H), 7.73-7.66 (m, 1H), 7.60 (d, J = 2.8 Hz, 1H), 6.97-6.91 (m, 1H), 6.87 (d, J = 5.2 Hz, 1H), 3.92 (s, 3H), 3.90-3.79 (m, 4H), 3.68-3.57 (m, 3H), 3.56-3.42 (m, 5H), 2.68-2.53 (m, 4H), 1.89-1.78 (m, 2H), 1.61-1.45 (m, 4H), 1.00-0.83 (m, 3H). 19 ¹ H-NMR (400 MHz, CHLOROFORM- d ) δ (ppm) 9.05 - 8.94 (m, 1H), 8.16 - 8.01 (m, 1H), 7.27 - 7.19 (m, 1H), 7.15 - 7.04 (m, 2H), 6.60 (t, J = 9.1 Hz, 1H), 5.44 - 5.25 (m, 1H), 4.45 - 4.30 (m, 2H), 3.96 - 3.71 (m, 3H), 2.86 - 2.72 (m, 5H), 2.30 - 2.16 (m, 4H), 1.96 - 1.83 (m, 4H), 1.73 - 1.60 (m, 4H). 20 ¹ H NMR (300 MHz, CHLOROFORM-d) δ (ppm) 8.96 (s, 1H), 7.94 (d, J = 5.5 Hz, 1H), 7.75 (s, 1H), 7.59 (s, 1H), 6.85-6.75 (m, 2H), 4.29-3.93 (m, 5H), 3.12 (s, 2H), 2.45 (s, 3H), 2.35-1.98 (m, 8H), 1.48-1.41 (m, 2H). twenty one ¹ H NMR (300 MHz, CHLOROFORM- d ) δ (ppm) 9.04-8.98 (m, 1H), 8.09-8.01 (m, 1H), 7.99-7.88 (m, 2H), 7.69-7.60 (m, 1H), 6.91-6.76 (m, 2H), 4.40-4.29 (m, 1H), 4.26-4.07 (m, 3H), 4.04-3.95 (m, 4H), 3.43 (s, 4H), 2.59-2.41 (m, 2H), 2.36-2.27 (m, 1H), 2.11-2.00 (m, 1H), 1.48-1.38 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). twenty two ¹ H-NMR (400 MHz, chloroform- d ) δ (ppm) 9.04-8.87 (m, 1H), 8.04-7.89 (m, 1H), 7.50-7.29 (m, 3H), 7.22-7.12 (m, 1H), 6.90-6.74 (m, 1H), 4.32-4.05 (m, 3H), 4.03-3.82 (m, 5H), 2.77-2.50 (m, 3H), 2.31-2.01 (m, 2H), 1.50-1.35 (m, 2H). twenty three ¹ H-NMR (400 MHz, chloroform- d ) δ (ppm) 8.99-8.92 (m, 1H), 7.93 (dd, J = 5.5, 1.5 Hz, 1H), 7.46- 7.36 (m, 2H), 7.35-7.29 (m, 1H), 7.24-7.15 (m, 1H), 6.80 (dd, J = 5.6, 1.5 Hz, 1H), 4.12-4.04 (m, 2H), 4.04-3.97 (m, 1H), 3.93 (s, 4H), 3.88- 3.83 (m, 1H), 3.57-3.48 (m, 1H), 3.43-3.36 (m, 1H), 3.36-3.29 (m, 2H), 2.86-2.76 (m, 3H), 2.66- 2.60 (m, 3H), 2.09-1.92 (m, 4H). twenty four ¹ H NMR (300 MHz, DMSO-d6) δ (ppm) 9.89 (s, 1H), 9.22 (s, 1H), 7.87 (d, J = 5.6 Hz, 1H), 7.72 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 5.5 Hz, 1H), 4.57 (s, 4H), 4.52 (s, 4H), 3.86 (s, 2H), 3.78 (s, 2H), 3.33-3.30 (s, 3H). 25 ¹ H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 2.7 Hz, 1H), 7.45 (s, 1H), 6.67 (d, J = 6.0 Hz, 1H), 4.25 (s, 4H), 3.81 (s, 1H), 3.63 (d, J = 12.1 Hz, 2H), 3.47(s, 1H), 3.07-2.78 (m, 5H),2.68-2.54 (m, 2H), 2.30 (s, 3H), 2.17-2.07 (m, 1H), 2.06-1.92 (m, 3H), 1.66-1.48 (m, 2H), 1.07-0.86 (m, 4H). 26 ¹ H NMR (300 MHz, DMSO-d6) δ (ppm) 9.47 (s, 1H), 9.04 (s, 1H), 7.94 (s, 1H), 7.53 (s, 1H), 6.77 (s, 1H), 4.82-4.67 (m, 1H), 4.48 (s, 4H), 4.10 (s, 4H), 3.21 (s, 2H), 3.12 (s, 2H), 3.03 (s, 3H), 2.65-2.56 (m, 2H), 2.56-2.54 (m, 2H), 2.34 (s, 3H), 2.17 (s, 3H). 27 ¹ H NMR (300 MHz, DMSO-d6) δ (ppm) 9.88 (s, 1H), 9.11 (s, 1H), 7.87 (d, J = 1.9 Hz, 1H), 7.55 -7.46 (m, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 0.9 Hz, 1H), 4.65 (d, J = 17.0 Hz, 4H), 4.38 (s, 4H), 3.30-3.25 (s, 4H), 3.00 (s, 3H), 2.38-2.32 (m, 3H), 2.19 (s, 3H). 28 ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 9.37(s, 1H), 9.03(s, 1H), 7.38(d, J = 8.7 Hz, 2H), 6.77 (s, 1H), 6.42 (d, J = 8.7 Hz, 2H), 4.49-4.45 (m, 1H), 3.95-3.91(m, 3H), 3.87(s, 4H), 3.24(s, 4H), 2.35-2.27(m, 4H), 2.18-2.06 (m, 4H), 1.27-1.21(m, 1H), 0.60-0.58 (m, 2H), 0.46-0.41 (m, 2H). 29 ¹ H NMR (400 MHz, CHLOROFORM- d ) δ (ppm) 8.89 (s, 1H), 7.69-7.61 (m, 1H), 7.39-7.31 (m, 1H), 7.28-7.22 (m, 2H), 6.65 (s, 1H), 4.51 (s, 4H), 4.12-4.00 (m, 8H), 3.87-3.75 (m, 1H), 3.46 (s, 4H), 2.94 (s, 3H), 2.47 (s, 3H), 2.37 (s, 3H). 30 ¹ H-NMR (400 MHz, chloroform- d ) δ (ppm) 9.44 (s, 1H), 9.04 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 0.9 Hz, 1H), 6.50-6.39 (m, 2H), 4.56-4.40 (m, 8H), 3.82 (s, 4H), 3.25 (s, 4H), 2.35 (s, 3H), 2.19 (s, 3H). 31 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 9.36(s, 1H), 9.17-9.09(m, 1H), 7.85-7.50(m, 1H), 7.30-7.21(m, 1H), 6.78(s, 1H), 4.65-4.55(m, 1H), 4.15(s, 4H), 3.11-2.98(m, 6H), 2.91-2.85(m, 4H), 2.35(s, 3H), 2.11-1.95(m, 3H) 32 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.95(s, 1H), 7.45(s, 1H), 6.68(s, 1H), 4.41(s, 4H), 3.99(s, 1H), 3.88(s, 1H), 3.75-3.61(m, 4H), 3.60-3.50(m, 2H), 3.15-3.0(m, 2H), 2.70-2.55(m, 1H), 2.35-2.25(m, 3H), 2.10-1.95(m, 2H), 1.65-1.55(m, 2H), 1.08-0.91(m, 4H). 33 ¹ H-NMR (400 MHz, chloroform- d ) δ (ppm) 8.94-8.77 (m, 1H), 7.76-7.64 (m, 1H), 7.62-7.53 (m, 1H), 6.81-6.70 (m, 1H), 6.67-6.60 (m, 1H), 4.69-4.56 (m, 1H), 4.27-4.11 (m, 2H), 4.13-4.05 (m, 1H), 4.03-3.89 (m, 1H), 3.46- 3.34 (m, 3H), 2.75-2.70 (m, 3H), 2.48-2.43 (m, 3H), 2.42-2.34 (m, 3H), 2.26-2.19 (m, 1H), 2.09-1.96 (m, 2H), 1.46-1.37 (m, 2H), 1.31-1.21 (m, 1H). 34 ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 9.31 (s, 1H), 9.01 (s, 1H), 7.40-7.30 (m, 2H), 6.74 (d, J = 0.9 Hz, 1H), 6.45-6.27 (m, 2H), 4.14-3.99 (m, 2H), 3.99-3.87 (m, 2H), 3.81 (s, 4H), 3.27 (s, 4H), 2.34 (s, 3H), 2.20 (s, 3H), 2.16-2.08 (m, 1H), 2.06-1.95 (m, 1H), 1.68-1.51 (m, 2H). 35 ¹ H NMR (300 MHz, DMSO-d6) δ (ppm) 9.24 (s, 1H), 8.96 (s, 1H), 7.36 (d, J = 8.6 Hz, 2H), 6.64 (s, 1H), 6.38 (d, J = 8.7 Hz, 2H), 3.78 (d, J = 3.8 Hz, 8H), 3.63-3.43 (m, 4H), 3.23(s, 4H), 2.30 (s, 3H), 2.17 (s, 3H), 1.82-1.72 (m, 2H), 1.53-1.44 (m, 4H). 36 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 9.42 (s, 1H), 9.06 (s, 1H), 7.85 (s, 1H), 7.52 (s, 1H), 6.79 (s, 1H), 4.18-3.87 (m, 6H), 2.36 (s, 3H), 2.18 (s, 7H), 2.12-2.04 (m, 1H), 1.69-1.60 (m, 2H), 0.69-0.64 (m, 2H), 0.59-0.54 (m, 2H). 37 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.35(s, 1H), 9.11(s, 1H), 7.85-7.71(m, 1H), 7.35-7.25(m, 1H),6.78(s, 1H), 4.65(s, 4H), 4.38-4.21(m, 4H), 3.61(s, 4H), 3.05-2.95(m, 3H), 2.65(s. 3H), 2.10 (s, 1H). 38 ¹ H NMR (400 MHz, CHLOROFORM- d ) δ (ppm) 8.91 (s, 1H), 7.79 (s, 1H), 7.59 (s, 1H), 6.77 (s, 1H), 6.70 (s, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.31-4.16 (m, 4H), 4.01 (d, J = 12.0 Hz, 1H), 2.48-2.34 (m, 10H), 2.21-2.11 (m, 1H), 1.16-1.07 (m, 1H), 0.77 (s, 4H), 0.71-0.59 (m, 4H). 39 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.38 (s, 1H), 9.18-9.09 (m, 1H), 7.82-7.55 (m, 1H), 7.32-7.21 (m, 1H), 6.81-6.75 (m, 1H), 4.70-4.60 (m, 5H), 4.15 (s, 4H), 3.10-2.98 (m, 5H), 2.95-2.88 (m, 2H), 2.35 (s, 3H), 2.01-1.95 (m, 2H). 40 ¹ H NMR (300 MHz, DMSO-d6) δ (ppm) 8.88 (s, 1H), 7.20 (s, 1H), 6.66 (s, 1H), 6.60 (s, 1H), 4.27 (s, 1H), 4.00 (s, 3H), 2.31 (s, 3H), 2.20-2.13 (m, 1H), 2.09 (s, 6H), 1.99 (d, J = 7.0 Hz, 4H), 1.80 (d, J = 13.2 Hz, 2H), 1.66-1.52 (m, 2H), 1.39 (s, 1H), 1.22 (s, 3H), 0.96- 0.84 (m, 2H). 43 ¹ H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 8.85-8.74 (m, 1H), 8.60 (s, 1H), 6.64-6.55 (m, 1H), 4.59-4.32 (m, 2H), 4.27-3.92 (m, 4H), 3.84-3.67 (m, 1H), 3.12-2.94 (m, 1H), 2.84-2.68 (m, 4H), 2.55 (d, J = 11.6 Hz, 1H), 2.43 (d, J = 3.2 Hz, 3H), 2.35-2.21 (m, 2H), 2.13-1.96 (m, 2H), 1.95-1.83 (m, 1H), 1.54-1.37 (m, 2H). 45 ¹ H-NMR (300 MHz, DMSO- d ₆ ) δ (ppm) 8.76 (s, 1H), 6.66-6.48 (m, 1H), 5.33 (d, J = 7.3 Hz, 1H), 4.39-4.30 (m, 1H), 4.29-4.19 (m, 1H), 4.18-4.00 (m, 3H), 2.55-2.36 (m, 5H), 2.19 (d, J = 6.8 Hz, 2H), 2.09-2.01 (m, 1H), 1.88-1.80 (m, 2H), 1.77-1.63 (m, 6H), 1.48-1.39 (m, 3H), 1.39-1.29 (m, 3H), 1.28-1.21 (m, 2H). 46 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.80 (s, 1H), 7.88 (s, 1H), 7.19 (s, 1H), 6.75 (t, J = 55.5 Hz, 1H), 4.37 (s, 4H), 3.87 (s, 1H), 3.63 (dd, J = 12.5, 4.5 Hz, 2H), 3.36 (s, 2H), 3.22 - 3.14 (m, 2H), 3.11 - 3.01 (m, 2H), 2.60 (tt, J = 7.8, 4.9 Hz, 1H), 2.21 (t, J = 7.2 Hz, 2H), 2.0 12.8 Hz, 2H), 1.63 (q, J = 11.3 Hz, 2H), 1.01 (dt, J = 7.9, 2.8 Hz, 2H), 0.98 - 0.92 (m, 2H). 47 ¹ H NMR (400 MHz, DMSO-d6) δ (ppm) 9.71 (s, 1H), 9.08 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 5.1 Hz, 1H), 4.24 (s, 4H), 3.95 (d, J = 8.0 Hz, 4H), 3.47 (s, 2H), 3.32 (d, J = 7.1 Hz, 1H), 2.96 (s, 1H), 2.86-2.77 (m, 1H), 2.35 (s, 3H), 2.14-2.01 (m, 2H), 1.98-1.91 (m, 1H), 0.49-0.43 (m, 2H), 0.42-0.37 (m, 2H). 48 ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.93 (s, 1H), 7.45 (s, 1H), 6.67 (s, 1H), 4.37 (s, 4H), 3.86 (s, 1H), 3.63 (d, J = 11.9 Hz, 2H), 3.45-3.37(m, 4H), 3.05 (t, J = 11.2 Hz, 2H), 2.68-2.56 (m, 1H), 2.31 (s, 3H), 2.06-1.98 (m, 2H), 1.87-1.80 (m, 1H), 1.70-1.55 (m, 2H), 1.06-0.91 (m, 4H), 0.39-0.29 (m, 2H), 0.24-0.17 (m, 2H). 49 ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 9.11-8.55 (m, 1H), 7.80-7.21 (m, 1H), 6.76-6.51 (m, 1H), 4.68-3.95 (m, 4H), 3.83 (s, 1H), 3.73-3.53 (m, 2H), 3.08-2.94 (m, 2H), 2.69 (s, 2H), 2.65-2.57 (m, 1H), 2.49-2.44 (m, 2H), 2.30 (s, 3H), 2.27-2.22 (m, 3H), 2.11-1.93 (m, 4H), 1.66-1.53 (m, 2H), 1.04-0.91 (m, 4H). 50 ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 9.28 (s, 1H), 8.31 (s, 2H), 7.67 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.1, 2.0 Hz, 1H), 7.27 (s, 1H), 7.21 (d, J = 8.1 Hz, 1H), 6.80 (t, J = 55.5 Hz, 1H), 4.34 (s, 4H), 3.98 (s, 2H), 3.94 (s, 2H), 3.25 (s, 2H), 3.10 (t, J = 7.1 Hz, 2H), 2.16 (t, J = 7.1 Hz, 9H), 2.11 - 2.01 (m, 1H), 0.53 - 0.38 (m, 4H). 51 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.92 (s, 1H), 7.40 (s, 1H), 6.66 (d, J = 7.9 Hz, 1H), 4.24 (s, 4H), 3.82 (s, 1H), 3.63-3.55 (m, 2H), 3.06 (d, J = 6.9 Hz, 2H), 2.94 (d, J = 14.2 Hz, 4H), 2.84-2.77 (m, 2H), 2.30 (s, 3H), 2.26-2.15 (m, 1H), 2.03-1.91 (m, 4H), 1.90-1.81 (m, 2H), 1.67-1.48 (m, 6H), 1.35-1.21 (m, 3H). 52 ¹ H-NMR (400 MHz, chloroform- d ) δ (ppm) 8.93-8.67 (m, 1H), 6.77-6.43 (m, 1H), 5.96 (s, H), 5.25-5.03 (m, 1H), 4.70-4.42 (m, 1H), 4.16-3.72 (m, 6H), 3.01-2.89 (m, 2H), 2.83 (s, 3H), 2.68-2.36 (m, 6H), 2.28-2.18 (m, 2H), 2.06-1.82 (m, 4H). 53 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.91 (s, 1H), 7.37 (s, 1H), 6.63 (s, 1H), 4.08 (s, 2H), 3.90 (s, 2H), 3.82 (d, J = 9.5 Hz, 1H), 3.59 (d, J = 12.0 Hz, 2H), 2.93-2.83 (m, 5H), 2.70-2.58 (m, 4H), 2.30 (s, 3H), 2.07- 1.99 (m, 4H), 1.59 (q, J = 11.3 Hz, 2H). 54 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.90 (s, 1H), 7.32 (s, 1H), 6.61 (s, 1H), 4.04 (s, 2H), 3.89-3.70 (m, 3H), 3.57 (d, J = 12.0 Hz, 2H), 2.91-2.78 (m, 5H), 2.30 (s, 3H), 2.04-1.93 (m, 2H), 1.89-1.80 (m, 2H), 1.64-1.57 (m, 2H), 0.62 (d, J = 6.4 Hz, 4H). 55 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.16 (s, 1H), 6.68 (t, J = 55.7 Hz, 1H), 4.39 (q, J = 9.5 Hz, 4H), 3.94 (s, 1H), 3.64 (d, J = 12.6 Hz, 2H), 3.27 (s, 2H), 3.17 (d, J = 7.2 Hz, 2H), 3.11 (t, J = 7.1 Hz, 2H), 3.01 (ddd, J = 13.0, 10.6, 2.9 Hz, 2H), 2.75 (p, J = 7.5 Hz, δ 5.1 - 5.7 (m, 1H), 2.17 (dd, J = 8.3, 6.4 Hz, 4H), 2.02 (dd, J = 13.2, 3.7 Hz, 2H), 1.97 - 1.81 (m, 4H), 1.72 - 1.59 (m, 2H). 56 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.94 (s, 1H), 7.43 (s, 1H), 6.69 (s, 1H), 5.47 (s, 1H), 4.39-4.08 (m, 3H), 3.82-3.71 (m, 1H), 3.69-3.58 (m, 2H), 3.04-2.90 (m, 2H), 2.68-2.61 (m, 1H), 2.35-2.21 (m, 3H), 2.15-1.97 (m, 2H), 1.70-1.52 (m, 2H), 1.30-1.17 (m, 2H), 1.08-0.92 (m, 4H), 0.51-0.39 (m, 4H). 57 ¹ H NMR (400 MHz, DMSO-d6) δ (ppm) 8.93 (s, 1H), 7.47 (s, 1H), 6.68 (d, J = 0.9 Hz, 1H), 4.67-4.44 (m, 3H), 4.16 (s, 2H), 3.84 (s, 1H), 3.63 (d, J = 11.9 Hz, 2H), 3.39-3.35 (m, 1H), 3.06-2.95 (m, 2H), 2.64-2.53 (m, 1H), 2.31 (s, 3H), 2.02 (d, J = 12.8 Hz, 2H), 1.65-1.50 (m, 2H), 1.03-0.89 (m, 4H), 0.60-0.56 (m, 2H), 0.55-0.42 (m, 2H). 58 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.93 (s, 1H), 7.41 (s, 1H), 7.09-6.67 (m, 2H), 4.93-4.89 (m, 1H),4.28-4.12 (m, 1H), 4.04-3.79 (m, 3H), 3.67-3.58 (m, 2H), 3.02-2.91 (m, 2H), 2.59-2.56 (m, 1H), 2.32 (s, 3H), 2.23-2.11 (m, 2H), 2.09-1.90 (m, 2H), 1.70-1.53 (m, 2H), 1.23 (s, 1H), 1.02-0.98 (m, 2H), 0.97-0.90 (m, 2H). 59 ¹ H NMR (400 MHz, DMSO-d6) δ (ppm) 8.89 (s, 1H), 7.38 (s, 1H), 6.61 (s, 1H), 4.14 (s, 2H), 3.91-3.68 (m, 5H), 3.15 (d, J = 6.7 Hz, 2H), 3.13-3.04 (m, 4H), 2.29 (s, 3H), 2.23 (s, 3H), 2.07-1.98 (m, 4H), 1.59-1.47 (m, 2H), 1.43 (s, 3H), 1.21-1.13 (m, 2H), 0.86 - 0.80 (m, 2H). 60 ¹ H NMR (DMSO-d ₆ , 499 MHz) δ 8.98 (s, 1H), 7.4-7.6 (m, 1H), 6.8-6.9 (m, 1H), 4.9-5.0 (m, 1H), 4.2-4.4 (m, 4H), 3.80 (d, 2H, J = 8.5 Hz), 3.60 (d, 2H, J = 12.3 Hz), 3.46 (d, 1H, J = 8.5 Hz), 2.8-3.0 (m, 5H), 2.04 (d, 2H, J = 12.3 Hz), 1.9-2.0 (m, 2H), 1.5-1.7 (m, 3H), 0.92 (m, 2H), 0.7-0.8 (m, 2H) 61 ¹ H NMR (400 MHz, DMSO-d6) δ (ppm) 8.95 (s, 1H), 7.48 (s, 1H), 6.69 (s, 1H), 4.67-4.13 (s,3H), 3.84 (s, 1H), 3.65 (d, J = 12.1 Hz, 2H), 2.98 (t, J = 11.3 Hz, 2H), 2.88 (t, J = 11.7 Hz, 2H), 2.71-2.63 (s,2H), 2.61-2.54 (m, 2H), 2.31 (s, 3H), 2.07 (s, 1H), 2.04 (d, J = 12.4 Hz, 2H), 1.97 (s, 2H), 1.64-1.51 (m, 2H), 1.04-0.96 (m, 2H), 0.96-0.90 (m, 2H). 62 ¹ H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.00 (s, 1H), 7.60 (s, 1H), 6.82 (s, 1H), 4.58-4.41 (m, 2H), 4.38-4.32 (m, 2H), 4.31-4.21 (m, 2H), 4.19-4.09 (m, 2H), 3.87 (s, 1H), 3.72-3.57 (m, 2H), 3.09-2.97 (m, 2H), 2.63-2.54 (m, 1H), 2.36 (s, 3H), 2.10-1.97 (m, 2H), 1.69-1.52 (m, 2H), 1.07-0.91 (m, 4H). 63 ¹ H NMR (400 MHz, CHLOROFORM- d ) δ (ppm) 9.00 (d, J = 14.1 Hz, 1H), 7.25-7.13 (m, 1H), 4.98-4.84 (m, 1H), 4.61-4.46(m, 1H), 4.01 (d, J = 12.0 Hz, 2H), 3.21-3.16 (m, 3H), 3.09-2.98 (m, 2H), 2.76-2.56 (m, 5H), 2.48-2.39 (m, 1H), 2.38-2.29 (m, 1H), 2.07-1.94(m, 2H), 1.92-1.82 (m, 2H), 1.51 (s, 2H), 1.42 (s, 1H), 1.35-1.26 (m, 2H), 1.25-1.20 (m, 2H), 1.08-1.00 (m, 2H). 64 1H NMR (400 MHz, CHLOROFORM-d) δ 8.79 (s, 1H), 6.66 (s, 1H), 5.18 (d, J = 7.6 Hz, 1H), 4.52 (s, 4H), 3.95 (s, 5H), 3.78 (d, J = 12.6 Hz, 2H), 3.57 (t, J = 5.1 Hz, 2H), 3.38 (s, 3H), 3.12 (dd, J = 18.5, 9.5 Hz, 4H), 2.99 (s, 2H), 2.89 (p, J = 7.6 Hz, 1H), 2.32 - 2.20 (m, 2H), 2.23 - 2.13 (m, 2H), 2.04 - 1.85 (m, 5H), 1.75 (t, J = 11.5 Hz, 2H), 0.99 (dt, J = 4.8, 2.9 Hz, 2H), 0.92 - 0.81 (m, 2H). 65 1H NMR (300 MHz, CHLOROFORM-d) δ 8.92 (s, 1H), 7.09 (s, 1H), 6.52 (t, J = 56.1 Hz, 1H), 5.36 - 5.20 (m, 1H), 4.78 - 4.13 (m, 4H), 4.09 - 3.95 (m, 1H), 3.88 - 3.64 (m, 2H), 3.22 (s, 2H), 3.14 - 2.95 (m, 3H), 2.86 (s, 3H), 2.32 - 2.18 (m, 2H), 1.98 (m, 2H), 1.83 - 1.54 (m, 4H). 67 ¹ H NMR (DMSO-d ₆ , 499 MHz) δ 8.99 (d, 1H, J = 8.2 Hz), 7.5-7.8 (m, 1H), 6.78 (s, 1H), 4.50 (br d, 1H, J = 7.4 Hz), 4.2-4.4 (m, 2H), 4.0-4.1 (m, 1H), 3.80 (br d, 1H, J = 8.8 Hz), 3.72 (br d, 1H, J = 8.2 Hz), 3.65 (br d, 2H, J = 11.0 Hz), 3.49 (br d, 1H, J = 8.2 Hz), 3.09 (td, 2H, J = 4.2, 8.1 Hz), 3.0-3.0 (m, 2H), 2.35 (d, 4H, J = 2.7 Hz), 2.0-2.1 (m, 2H), 1.5-1.6 (m, 5H), 1.23 (s, 3H), 1.04 (d, 4H, J = 2.5 Hz) 68 ¹ H NMR (methanol-d4, 499 MHz) δ 8.9-9.0 (m, 1H), 6.8-6.9 (m, 1H), 5.1-5.3 (m, 2H), 4.9-4.7 (m, 2H), 3.8-3.8 (m, 2H), 3.0-3.1 (m, 2H), 2.60 (br d, 2H, J=3.6 Hz), 2.5-2.5 (m, 1H), 2.46 (s, 2H), 2.1-2.2 (m, 2H), 1.6-1.7 (m, 2H), 1.51 (d, 1H, J=4.7 Hz), 1.0-1.1 (m, 4H) 69 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.95 (s, 1H), 7.22-7.11 (m, 1H), 5.31 (s, 1H), 4.65-4.51 (m, 1H), 4.41-4.26 (m, 1H), 4.18-3.99 (m, 1H), 3.87-3.68 (m, 3H), 3.52 (s, 1H), 3.11-2.93 (m, 2H), 2.93-2.78 (m, 4H), 2.76-2.68 (m, 2H), 2.44-2.16 (m, 5H), 1.87-1.60 (m, 5H), 1.19 (s, 1H). 70 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.93 (s, 1H), 7.16 (s, 1H), 5.30-5.20 (m, 1H), 4.12-3.91 (m, 2H), 3.87-3.67 (m, 4H), 3.19-2.98 (m, 4H), 2.96-2.80 (m, 5H), 2.61-2.49 (m, 4H), 2.34-2.20 (m, 3H), 2.17-2.00 (m, 1H), 1.83-1.65 (m, 2H), 1.15-1.05 (m, 2H), 1.02-0.93 (m, 2H). 80 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.15 (s, 1H), 7.42 (s, 1H), 4.17 (dd, J = 10.4, 6.4 Hz, 2H), 4.07 (d, J = 6.3 Hz, 2H), 3.92 (s, 1H), 3.60 (d, J = 12.3 Hz, 2H), 3.51 (t, J = 4.8 Hz, 2H), 3.35 (t, J = 5.6 Hz, 2H), 3.29 (s, 3H), 3.18 (d, J = 7.3 Hz, 2H), 3.00 (s, 2H), 2.73 (q, J = 8.0, 7.0 Hz, δ 5.1 - 1.4 (m, 5H), 2.60 (d, J = 8.6 Hz, 2H), 2.24 - 2.07 (m, 4H), 2.01 (s, 2H), 1.95 - 1.77 (m, 5H), 1.62 (m, 2H), 1.00 - 0.91 (m, 4H). 83 ¹ H NMR (400 MHz, DMSO-d6) δ (ppm) 9.88 (s, 1H), 9.13 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.79 (s, 1H), 5.52 (s, 1H), 4.44 (s, 2H), 4.21 (s, 2H), 4.10 (d, J = 9.5 Hz, 2H), 2.90 (s, 3H), 2.36 (s, 3H), 1.29-1.18 (m, 1H), 0.50-0.42 (m, 2H), 0.41-0.35 (m, 2H). 84 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.93 (s, 1H), 7.14 (s, 1H), 5.25 (s, 1H), 4.20-3.90 (m, 2H), 3.87-3.64 (m, 5H), 3.14-2.97 (m, 2H), 2.85 (s, 3H), 2.76-2.54 (m, 9H), 2.53-2.38 (m, 4H), 2.33-2.22 (m, 2H), 1.81-1.68 (m, 2H). 85 ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.96 (s, 1H), 7.48 (s, 1H), 6.73 (s, 1H), 4.57-4.36 (m, 2H), 4.28-4.07 (m, 2H), 3.92-3.76 (m, 1H), 3.66-3.52 (m, 2H), 3.25 (s, 2H), 3.16 (t, J = 14.3 Hz, 2H), 3.02-2.81 (m, 6H), 2.33 (s, 3H), 2.08-1.95 (m, 2H), 1.70-1.53 (m, 2H). 86 ¹ H NMR (400 MHz, CDCL ₃ ) δ (ppm) 8.69 (s, 1H), 6.48 (s, 1H), 5.68-5.61 (m, 1H), 4.62-4.50 (m, 2H), 4.42-4.38 (m, 2H), 4.31-4.20 (m, 2H), 4.14-4.08 (m, 1H), 4.04- 3.96 (m, 2H), 3.72-3.65 (m, 1H), 3.52-3.46 (m, 1H), 3.30-3.22 (m, 1H), 2.42 (s, 3H), 2.13-2.08 (m, 1H), 1.75-1.61 (m, 1H), 1.33-1.27 (m, 1H), 0.64- 0.52 (m, 2H), 0.50-0.44 (m, 2H). 87 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.92 (s, 1H), 8.30 (s, 1H), 7.77 (s, 1H), 7.46 (s, 1H),6.67 (s, 1H), 4.37-4.24 (m, 2H), 4.19-4.15 (m, 1H), 3.93 (s, 3H), 3.67-3.50 (m, 3H), 2.83 -2.78(m, 2H), 2.67-2.61 (m, 2H), 2.50-2.41 (m, 4H), 2.33-2.30 (m, 3H), 2.04-2.01 (m, 2H), 1.92 (s, 2H), 1.65-1.57 (m, 2H). 88 ¹ H NMR (400 MHz, chloroform- d ) δ 8.97-8.95 (m, 2H), 7.29-7.26 (m, 1H), 4.63-4.60 (m, 1H), 4.10-3.83 (m, 3H), 2.99-2.93 (m, 4H), 2.89-2.87 (m, 4H), 2.72-2.70 (m, 3H), 2.54-2.20 (m, 4H), 1.84-1.78 (m,3H), 0.47-0.41 (m, 4H). 89 ¹ H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 2H), 8.98 (s, 1H), 8.34 (s, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 6.81 (s, 1H), 4.42 (s, 2H), 4.29 (s, 2H), 4.22 (d, J = 11.6 Hz, 2H), 4.09 (d, J = 11.5 Hz, 2H), 3.92 (s, 3H), 3.72 (s, 1H), 3.49 (d, J = 11.3 Hz, 2H), 2.53 (s, 2H), 2.35 (s, 3H), 2.0 2H), 1.69-1.57 (m, 2H). 90 ¹ H-NMR (400 MHz, chloroform- d ) δ (ppm) 8.92 (s, 1H), 7.09 (s, 1H), 6.52 (t, J = 56.1 Hz, 1H), 5.46-5.20 (m, 1H), 5.01-4.45 (m, 2H), 4.40-4.13 (m, 2H), 4.06-3.94 (m, 1H), 3.90-3.75 (m, 2H), 3.10-2.79 (m, 10H), 2.32-2.21 (m, 2H), 2.18-2.04 (m, 2H), 1.85-1.74 (m, 2H). 91 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.97 (s, 1H), 7.49 (s, 1H), 6.73 (s, 1H), 6.58 (s, 1H), 6.16 (s, 1H), 4.49 (s, 2H), 4.19 (s, 2H), 3.82 (s, 1H), 3.58 (d, J = 12.2 Hz, 2H), 2.95-2.84 (m, 5H), 2.33 (s, 3H), 2.02 (d, J = 12.0 Hz, 2H), 1.66-1.54 (m, 2H). 92 ¹ H NMR (400 MHz, CDCL ₃ ) δ (ppm) 8.83 (s, 1H), 6.68 (s, 1H), 5.25-5.24 (m, 1H), 4.47-4.41 (m, 2H), 4.37-4.34 (m, 2H), 4.12-4.09 (m, 2H), 3.84-3.81 (m, 2H), 3.62-3.51 (m, 2H), 3.03-2.97 (m, 2H), 2.86 (s, 3H), 2.45 (s, 4H), 2.26-2.24 (m, 2H),1.78-1.70 (m, 2H), 1.28 (s, 1H). 93 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.16 (s, 1H), 7.70 (s, 1H), 7.37 (s, 1H), 6.06-5.85 (m, 2H), 4.08-3.86 (m, 2H), 3.60-3.50 (m, 2H), 2.96-2.83 (m, 5H), 2.72-2.62 (m, 2H), 2.59-2.52 (m, 4H), 2.14-2.01 (m, 3H), 1.67-1.55 (m, 2H). 94 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 7.96 (s, 1H), 7.52 (s, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 4.40-4.11 (m, 4H), 3.96 (s, 3H), 3.82-3.59 (m, 5H), 3.38-3.32 (m, 2H), 2.73-2.57 (m, 3H), 2.33 (s, 3H), 2.09-1.95 (m, 2H), 1.70-1.46 (m, 2H). 95 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.99 (s, 1H), 7.56 (s, 1H), 6.81 (s, 1H), 4.40-4.37 (m, 4H), 4.32-4.06 (m, 2H), 4.03-3.85 (m, 3H), 3.66-3.63 (m, 2H), 3.10-2.97 (m, 4H), 2.35 (s, 3H), 2.03-2.01 (m, 2H), 1.61-1.53 (m, 2H), 1.25-1.21 (m, 4H). 96 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.98 (s, 1H), 7.54 (s, 1H), 6.78 (s, 1H), 4.40-4.20 (m, 4H), 4.10 (q, J = 5.2 Hz, 1H), 3.84 (s, 1H), 3.66-3.55 (m, 2H), 3.21 (d, J = 7.7 Hz, 2H), 3.17 (d, J = 5.2 Hz, 3H), 2.88 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 2.10-1.98 (m, 2H), 1.67 - 1.52 (m, 2H). 97 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.96 (s, 1H), 8.34 (s, 1H), 7.77 (d, J = 0.6 Hz, 1H), 7.53 (s, 1H), 6.76 (d, J = 0.9 Hz, 1H), 4.28 (s, 2H), 4.23 (s, 1H), 3.92 (s, 3H), 3.70 (s, 1H), 3.55 (d, J = 11.6 Hz, 2H), 3.39 (d, J = 7.8 Hz, 2H), 3.18 (s, 2H), 2.45 (d, J = 11.4 Hz, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 2.08 (s, 2H), 2.06-1.99 (m, 2H), 1.69-1.59 (m, 2H). 98 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.97-8.95 (m, 1H), 7.54-7.44 (m, 1H), 6.74-6.72 (m, 1H), 5.75-5.33 (m, 4H), 4.38-4.20 (m, 4H), 3.84-3.80 (m, 1H), 3.58-3.49 (m, 4H), 2.88-2.86 (m, 5H), 2.33 (s, 3H), 2.03-2.00 (m, 2H), 1.60-1.57 (m, 2H). 99 ¹ H NMR (400 MHz, CD ₃ OD) δ 8.04 (s, 1H), 7.32 (s, 1H), 4.10-3.99 (m, 1H), 3.80-3.70 (m, 2H), 3.24-3.13 (m, 2H), 3.09-2.96 (m, 2H), 2.91-2.88 (m, 4H), 2.84-2.77 (m, 2H), 2.61 (s, 3H), 2.52-2.44 (m, 1H), 2.36-2.15 (m, 4H), 1.84-1.66 (m, 2H), 0.94-0.83 (m, 2H). 100 ¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.04-8.68 (m, 1H), 7.45-7.11 (m, 1H), 6.64 (d, J = 4.1 Hz, 1H), 6.03 (t, J = 55.8 Hz, 1H), 5.32-5.06 (m, 1H), 4.92-4.68 (m, 1H), 4.34 (s, 3H), 4.10-3.91 (m, 1H), 3.89-3.73 (m, 2H), 3.51-3.07 (m, 4H), 3.05-2.92 (m, 2H), 2.91-2.78 (m, 3H), 2.73-2.56 (m, 1H), 2.56-2.35 (m, 3H), 2.22 (s, 2H), 1.83-1.65 (m, 2H). 101 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.97 (s, 1H), 7.49 (s, 1H), 6.74 (s, 1H), 4.48 (s, 2H), 4.19 (s, 2H), 3.83 (s, 1H), 3.61-3.52 (m, 2H), 3.03-2.92 (m, 4H), 2.91-2.83 (m, 5H), 2.33 (s, 3H), 2.29 (s, 3H), 2.06-1.97 (m, 2H), 1.67-1.54 (m, 2H). 102 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 9.03-8.92 (m, 1H), 7.55 (s, 1H), 6.81-6.72 (m, 1H), 4.44-4.15 (m, 4H), 3.84 (s, 1H), 3.67 (d, J = 12.0 Hz, 2H), 3.34-3.30 (m, 2H), 3.20 (d, J = 7.6 Hz, 2H), 3.05-2.93 (m, 2H), 2.63-2.54 (m, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 2.12-1.98 (m, 2H), 1.67-1.50 (m, 2H), 1.04-0.91 (m, 4H). 103 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (s, 1H), 7.45-7.41 (m, 1H), 6.70 (s, 1H), 5.30-5.15 (m, 1H), 4.54-4.17 (m, 3H), 3.82 (s, 1H), 3.57-3.54 (m, 2H), 2.96-2.88 (m, 5H),2.84-2.82 (m, 2H), 2.67-2.50 (m, 3H), 2.49-2.28 (m, 6H), 2.12-1.95 (m, 2H), 1.71-1.52 (m, 2H). 104 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (s, 1H), 7.49-7.43 (m, 1H), 6.70 (s, 1H), 5.30-5.15 (m, 1H), 4.53-4.13 (m, 3H), 3.82 (s, 1H), 3.58-3.56 (m, 2H), 3.01-2.82 (m, 7H),2.67-2.63 (m, 3H), 2.50-2.28 (m, 6H), 2.02-1.99 (m, 2H), 1.71-1.59 (m, 2H).

In some embodiments, the compounds of the present invention are in Table 2. Table 2 Compound No. Structure Name 8A 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-5-fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 9A 6-(Difluoromethyl)-8-(6-(2-methoxyethyl)-2,6-diazaspiro[3.3]hept-2-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 10A 6-(Difluoromethyl)-8-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine 11A 8-(6-cyclopropyl-2,6-diazaspiro[3.3]hept-2-yl)-6-(difluoromethyl)-N-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrido[3,4-d]pyrimidin-2-amine 12A 2-(6-(Difluoromethyl)-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2-azaspiro[3.3]heptan-6-ol 13A 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 14A N-(1-(Methylsulfonyl)piperidin-4-yl)-8-(8-oxa-2-azaspiro[4.5]dec-2-yl)pyrido[3,4-d]pyrimidin-2-amine 15A N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)-8-(8-oxa-2-azaspiro[4.5]dec-2-yl)pyrido[3,4-d]pyrimidin-2-amine 16A 8-(4'-Fluorospiro[cyclopentane-1,3'-indolin]-1'-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine 17A (3aR,8bR)-2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2,3,3a,8b-tetrahydro-1H-benzo[4,5]thieno[2,3-c]pyrrole 4,4-dioxide 18A 3-Cyclopropyl-1-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyrrolidine-3-carbonitrile 19A 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-2-amine 20A 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine 21A 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(2-methylisoindolin-5-yl)pyrido[3,4-d]pyrimidin-2-amine 22A 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrroline-2-yl)pyrido[3,4-d]pyrimidin-2-amine 23A 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-N-(1-(methylsulfonyl)azacyclobut-3-yl)pyrido[3,4-d]pyrimidin-2-amine 24A N-((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)-8-(7-(methylsulfonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine 25A N-(2-methylisoindolin-5-yl)-8-(7-(methylsulfonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine 26A 6-(2-((2-methylisoindolin-5-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide 27A 6-Methyl-N-(1-(2-methyl-2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-8-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)pyrido[3,4-d]pyrimidin-2-amine 28A 6-methyl-8-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(2-(1-(methylsulfonyl)azepinecyclobut-3-yl)isoindolin-5-yl)pyrido[3,4-d]pyrimidin-2-amine 29A 6-Methyl-8-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(2-(methylsulfonyl)isoindol-5-yl)pyrido[3,4-d]pyrimidin-2-amine 30A 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-6-methyl-N-(1-(2-methyl-2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine 31A 8-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-6-methyl-N-(4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine 32A 3-Cyclopropyl-1-(6-methyl-2-((4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyrrolidine-3-carbonitrile 33A 3-Cyclopropyl-1-(6-methyl-2-((1-(2-methyl-2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyrrolidine-3-carbonitrile 34A 6-Methyl-N-(4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)phenyl)-8-(8-oxa-2-azaspiro[4.5]dec-2-yl)pyrido[3,4-d]pyrimidin-2-amine 35A 6-(6-methyl-2-((4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide Example 5 : Biochemical Analysis of CDK1 / Cyclin B1 ADP - Glo Kinase Assay

The purpose of the CDK1/cyclin B1 assay is to evaluate the inhibition (% inhibition and IC ₅₀ values) of small molecule inhibitors by using the luminescence-based ADP-Glo assay. CDK1/cyclin B1 catalyzes the generation of ADP from ATP. The ADP-Glo assay monitors the generation of ADP in biochemical reactions. ADP-Glo is performed in two steps after the kinase reaction is complete: in the first step, the kinase reaction is terminated and the remaining ATP is depleted, and in the second step, the generated ADP is converted to ATP and the newly generated ATP is converted to light output using a luciferase/luciferin reaction. The luminescence signal generated is proportional to the concentration of ADP generated and is correlated with kinase activity. CDK1/cyclin B1 was purchased from Carna (Catalog No. 04-102). A typical reaction solution (10 uL final reaction volume) contains 2% DMSO (± inhibitor), 10 mM MgCl2, 1 mM EGTA, 0.05% BSA, 2 mM DTT, 80 uM ATP (ATP Km = 78.6 uM), 0.01% Brig-35, 0.75 uM substrate and 4.917 nM CDK1/cyclin B1 enzyme complex in 50 mM HEPES buffer (pH 7.5). After 30 minutes of pre-incubation of enzyme and inhibitor in the reaction mixture at room temperature, the assay is started by adding the ATP-containing substrate solution. The reaction is stopped after 90 minutes at room temperature by adding 10 uL ADP-GLO reagent. After the 90-minute incubation, 20 uL kinase probe reagent is added. Samples were incubated for 40 minutes after which the well luminescence was measured on an Envision microplate reader. _IC50 determinations were made based on curves of fractionation velocity as a function of inhibitor concentration fitted to a 4-parameter _IC50 equation. CDK2 / Cyclin E1 Full-Length ADP - Glo Kinase Assay

The purpose of the CDK2/periodic protein E1 assay is to evaluate the inhibition (% inhibition and IC ₅₀ value) of small molecule inhibitors by using the luminescence-based ADP-Glo assay. The full-length CDK2/periodic protein E1 catalyzes the generation of ADP from ATP. The ADP-Glo assay monitors the generation of ADP in biochemical reactions. ADP-Glo is performed in two steps after the kinase reaction is completed: in the first step, the kinase reaction is terminated and the remaining ATP is depleted, and in the second step, the generated ADP is converted to ATP and the newly generated ATP is converted to light output using a luciferase/luciferin reaction. The luminescent signal generated is proportional to the ADP concentration generated and is related to the kinase activity. CDK2/periodic protein E1 was purchased from Eurofins (Catalog No. 14-475M). A typical reaction solution (10 uL final reaction volume) contains 2% DMSO (± inhibitor), 10 mM MgCl2, 1 mM EGTA, 0.05% BSA, 2 mM DTT, 20 uM ATP (ATP Km = 64.78 uM), 0.01% Brig-35, 0.75 uM substrate and 0.328 nM wild-type full-length CDK2/cyclin E1 enzyme complex in 50 mM HEPES buffer (pH 7.5). After 30 minutes of pre-incubation of enzyme and inhibitor in the reaction mixture at room temperature, the assay is started by adding the ATP-containing substrate solution. The reaction is stopped after 90 minutes at room temperature by adding 10 uL ADP-GLO reagent. After the 90-minute incubation, 20 uL kinase probe reagent is added. The samples were incubated for 40 minutes after which the well luminescence was measured on an Envision microplate reader. _IC50 determinations were made based on curves of fractionation velocity as a function of inhibitor concentration fitted to a 4-parameter _IC50 equation. CDK4 / Cyclin D1 CHEF Assay

The purpose of the CDK4/Cyclin D1 assay is to evaluate the inhibition (% inhibition and _IC50 values) of small molecule inhibitors by using the chelate enhanced fluorescence (CHEF) assay. In the CHEF assay, phosphorylation of a peptide substrate results in a proportional increase in fluorescence. The CHEF kinase assay uses a peptide substrate containing a synthetic α-amino acid flanked by an 8-hydroxyquinoline derivative (sulfonamido-oxide, Sox). Upon phosphorylation of adjacent serine, threonine, or tyrosine and in the presence of Mg(II), the spectral properties of the Sox residue change, resulting in emission of light at a wavelength of 485 nm when excited with a light source at a wavelength of 360 nm. CDK4/Cyclin D1 catalyzes the transfer of a phosphogroup to the SOX-labeled substrate peptide AQT0258 from Assayquant Technologies. A typical reaction solution contains 2% DMSO (+/- inhibitors), 10 mM MgCl2, 1 mM DTT, 200 uM ATP (ATP Km = 195.2 uM), 0.012% Brig-35, 10 uM AQT0258 peptide, 0.02% BSA, 1% glycerol, 0.55 mM EGTA, 2.5 nM CDK4/cyclin D1 in 54 mM HEPES buffer (pH 7.5). After pre-incubation of enzyme and inhibitor in the reaction mixture for 30 minutes at 22°C, the reaction is started by adding the substrate solution. The reaction is allowed to proceed for 3 hours at 22°C and the reaction is subsequently read by fluorescence. _IC50 determinations were performed based on curves of fractionation rate as a function of inhibitor concentration fitted to a 4-parameter _IC50 equation. CDK4/ cyclin D1 mobility shift assay (MSA)

The purpose of the CDK4/cyclin D1 assay is to assess inhibition (% inhibition and IC ₅₀ values) in the presence of small molecule inhibitors by using a fluorescence-based microfluidic mobility shift assay. CDK4/cyclin D1 catalyzes the generation of ADP from ATP with the concomitant transfer of the phospho group to the substrate peptide 5-FAM-Dyrktide (5-FAM-RRRFRPASPLRGPPK) (Perkin Elmer Peptide 34). Following the kinase reaction, the mobility shift assay (MSA) electrophoretically separates the fluorescently labeled peptides (substrate and phosphorylated product). Both substrate and product are measured, and the ratio of these values is used to generate the % conversion of substrate to product by the LabChip EZ reader. A typical reaction solution contains 2% DMSO (+/- inhibitors), 10 mM MgCl2, 1 mM EGTA, 0.05% BSA, 2 mM DTT, 0.2 mM ATP, 0.01% Brig-35, 1.5 uM 5-FAM-Dyrktide, 2.5 nM CDK4/cyclin D1 in 50 mM HEPES buffer (pH 7.5). After 30 minutes of pre-incubation of enzyme and inhibitor in the reaction mixture at 22°C, the reaction was started by adding the substrate solution. The reaction was stopped after 180 minutes by adding 75 uL of 500 mM EDTA and measured on a Perkin Elmer EZ reader instrument. _IC50 determinations were performed based on curves of fractionation rate as a function of inhibitor concentration fitted to a 4-parameter _IC50 equation. CDK6 / Cyclin D3 ADP - Glo Kinase Assay

The purpose of the CDK6/cyclin D3 assay is to assess inhibition (% inhibition and IC ₅₀ values) in the presence of small molecule inhibitors by using the luminescence-based ADP-Glo assay. CDK6/cyclin D3 catalyzes the generation of ADP from ATP. The ADP-Glo assay monitors the generation of ADP in biochemical reactions. ADP-Glo is performed in two steps after the kinase reaction is complete: in the first step, the kinase reaction is terminated and the remaining ATP is depleted, and in the second step, the generated ADP is converted to ATP and the newly generated ATP is converted to light output using a luciferase/luciferin reaction. The luminescent signal generated is proportional to the concentration of ADP generated and is correlated with kinase activity. CDK6/cyclin D3 was purchased from Carna. A typical reaction solution (10 uL final reaction volume) contains 2% DMSO (± inhibitor), 10 mM MgCI2, 1 mM EGTA, 0.05% BSA, 2 mM DTT, 100 uM ATP (ATP Km = 291.7 uM), 0.01% Brig-35, 0.75 uM substrate and 5 nM wild-type CDK6/cyclin D3 enzyme complex in 50 mM HEPES buffer (pH 7.5). After 30 minutes of pre-incubation of enzyme and inhibitor in the reaction mixture at room temperature, the assay is started by adding the ATP-containing substrate solution. The reaction is stopped after 90 minutes at room temperature by adding 10 uL ADP-GLO reagent. After the 90-minute incubation, 20 uL kinase probe reagent is added. The samples were incubated for 40 minutes, after which the plate well luminescence was measured on an Envision microplate reader. _IC50 determinations were made based on curves of fractionation rate as a function of inhibitor concentration fitted to a 4-parameter _IC50 equation. Cell Growth Inhibition

MCF-7 and OVCAR-3 cells were used to evaluate the antiproliferative activity of CDK inhibitors. MCF-7 (ATCC, HTB-22) cells are epithelial cells from female patients with ER+ metastatic adenocarcinoma. OVCAR-3 (ATCC, HTB-161) cells are derived from malignant ascites of patients with ovarian cancer and are known to have CCNE1 expansion. Both cell lines were maintained in RPMI medium supplemented with 10% fetal bovine serum. For cell growth inhibition analysis, CDK inhibitors in DMSO solution were dispensed into 384-well plates (Corning #3765) using Echo 655 (Beckman Coulter) or Tecan D300e (HP), and the 384-well plates were UV sterilized prior to analysis. Inhibitors were typically tested in the concentration range of 10-10,000 nM using semi-logarithmic serial dilutions. MCF-7 or OVCAR-3 (500 cells/30 µL/well) were added to each well using a Multidrop Combi (ThermoFisher) using standard cassettes. The assay plates with cells were incubated for 6 days at 37°C, 5% CO _2. At the end of the 6-day treatment, 30 µL CellTiterGlo 2.0 (Promega) was added to each well and the luminescence signal was read using a CLARIOstar plus (BMG). The cell growth inhibition percentage (CGI%) was calculated using the following formula: CGI% = 100 - 100× luminescence _sample /luminescence _control . The half-maximal inhibitory concentration (IC50) was determined by nonlinear curve fitting (four parameters, variable slope).

Certain compounds of the present invention have _IC50 values as shown in Table 3. All _IC50 values in Table 3 are reported as follows: ++++ = _IC50 < 200 nM; +++ = 200 nM < IC50 < 500 nM; ++ = 500 nM < IC50 < 2000 nM; + = IC50 > 2000 nMTable 3 Compound No. CDK1 Cyclin B1 IC ₅₀ nM CDK2/ Cyclin E1 IC ₅₀ nM CDK4/ Cyclin D1 MSA IC ₅₀ nM CDK4/ Cyclin D1 AQT IC ₅₀ nM CDK6/ Cyclin D3 IC ₅₀ nM MCF-7 cells IC ₅₀ nM OVCAR-3 cells IC ₅₀ nM 1 ++ ++++ ++++ +++ ++ + 2 ++++ ++++ ++++ ++++ ++ ++ 3 ++++ ++++ ++++ ++++ ++ ++++ 4 +++ ++++ ++++ ++++ +++ ++ 5 ++++ ++++ ++++ ++++ ++ ++ 6 + ++ ++++ ++++ ++ + 7 +++ ++++ ++++ ++++ ++ ++ 8 +++ ++++ ++ ++++ 9 +++ ++++ ++ ++ 10 + ++++ ++++ ++++ ++ ++ 11 ++++ ++++ ++++ ++++ ++ +++ 12 ++++ ++++ ++++ ++++ 13 ++++ ++++ ++++ ++++ 14 +++ ++++ ++++ ++++ + + 15 + ++ ++ + + + 16 ++++ ++++ ++++ ++++ ++ ++ 17 + +++ ++++ +++ ++ ++ 18 + ++ ++++ ++++ +++ + 19 + ++++ ++ + + + 20 ++ ++++ ++++ ++++ ++ +++ twenty one + +++ ++++ ++++ twenty two ++++ ++++ ++++ ++++ +++ +++ twenty three ++ ++++ ++++ ++++ ++++ ++++ twenty four ++ ++++ ++++ ++++ ++ ++ 25 +++ ++++ ++++ ++++ +++ +++ 26 + +++ +++ ++ + + 27 ++ ++++ ++ ++ + ++ 28 ++ ++++ ++++ ++++ ++ ++ 29 + +++ ++++ ++ + + 30 + +++ +++ +++ + + 31 + ++++ + + + + 32 ++ ++++ ++++ ++++ ++ ++ 33 ++ +++ ++++ ++++ ++ ++ 34 ++ ++++ ++++ ++++ ++ ++ 35 + +++ ++++ ++++ ++ ++ 36 + +++ +++ ++ + + 37 + +++ + + + + 38 + ++++ ++ + + ++ 39 + ++++ +++ + ++ + 40 + ++++ ++++ ++++ ++ ++ 41 ++++ ++++ ++++ ++++ + + 42 + ++++ ++++ ++ ++ ++ 43 + ++ ++++ +++ ++ ++ 44 + + +++ ++ + + 45 + + ++++ ++ + + 46 ++++ ++++ ++++ ++++ ++ ++ 47 ++ ++++ ++++ ++++ ++ ++ 48 ++ ++++ ++++ +++ + + 49 ++ ++++ ++++ +++ ++ ++ 50 ++ ++++ ++++ ++++ ++ ++ 51 ++ ++++ ++++ +++ ++ ++ 52 ++++ ++++ ++++ ++++ + ++ 53 + ++++ ++++ ++++ + + 54 ++++ ++++ ++++ ++++ + ++ 55 ++++ ++++ ++++ ++++ +++ ++ 56 ++++ ++++ ++++ ++++ ++ ++ 57 +++ ++++ ++++ ++++ + + 58 ++++ ++++ ++++ ++++ ++ ++ 59 ++ ++++ ++++ ++++ ++ ++ 60 ++++ ++++ ++++ ++++ ++ + 61 ++++ ++++ ++++ ++++ ++ ++ 62 ++++ ++++ ++++ ++++ ++ ++ 63 + +++ ++ + + + 64 ++ ++++ ++++ +++ + + 65 ++++ ++++ ++++ ++++ +++ +++ 66 ++ ++++ ++++ ++++ ++ ++ 67 +++ ++++ ++++ +++ + + 68 + ++++ +++ ++ 69 ++++ ++++ ++++ ++++ 70 ++++ ++++ ++++ ++++ ++ ++ 71 +++ ++++ ++++ ++++ + + 72 ++ ++++ +++ +++ + + 73 ++ ++++ ++++ +++ + + 74 ++ ++++ +++ +++ + + 75 + ++++ ++++ ++++ + + 76 +++ ++++ ++++ ++++ ++ + 77 +++ ++++ ++++ ++++ + + 78 +++ ++++ ++++ +++ ++ ++ 79 +++ ++++ ++++ +++ + ++ 80 ++ ++++ ++++ ++++ + + 81 +++ ++++ ++++ +++ 82 +++ ++++ +++ +++ 83 +++ ++++ ++++ ++++ + + 84 +++ ++++ ++++ ++++ ++ ++ 85 ++++ ++++ ++++ ++++ ++ ++ 86 + +++ ++++ +++ + + 87 ++++ ++++ ++++ ++++ ++ +++ 88 +++ ++++ ++++ ++++ 89 ++++ ++++ ++++ ++++ ++ +++ 90 ++++ ++++ ++++ ++++ ++ ++ 91 ++++ ++++ ++++ ++++ ++ +++ 92 ++++ ++++ ++++ ++++ ++ ++ 93 ++++ ++++ ++++ ++++ ++ ++ 94 ++++ ++++ ++++ ++++ ++ +++ 95 ++++ ++++ ++++ ++++ ++ ++ 96 ++++ ++++ ++++ ++++ +++ ++ 97 ++++ ++++ ++++ ++++ ++ +++ 98 +++ ++++ ++++ +++ 99 ++++ ++++ ++++ ++++ 100 ++++ ++++ ++++ ++++ 101 +++ ++++ ++++ ++++ 102 ++++ ++++ ++++ ++++ 103 ++ ++++ ++++ ++++ 104 ++ ++++ ++++ +++

Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions will now occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used to practice the present invention. It is intended that the following claims define the scope of the present invention, and that methods and structures within the scope of these claims and their equivalents are covered thereby.

Claims (76)

A compound or a pharmaceutically acceptable salt or solvent thereof, which has a structure of formula (I0): wherein A is a ring selected from the following: an optionally substituted carbon ring, an optionally substituted 4- to 8-membered heterocyclic ring, an optionally substituted tetrahydro-triazolopyrainze, and an optionally substituted isoindoline; ^Z0 is -C(H)- or nitrogen; each of ^Z1 , ^Z2 , and ^Y1 is independently selected from -C( ^R2 ) _2- , -C(O)-, ^-NR3- , -N(C(O) ^R2 )-, -NS( _O2 ) ^R2 , -O-, -S-, -S(O)-, and -S(O) _2- ; each of a and b is independently selected from 1, 2, 3, and 4; each ^R1 is independently selected from halogen, -CN, _-NO2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic ring and optionally substituted heterocyclic ring; m is selected from 0 to 5; each R ² is independently selected from hydrogen, halogen, -CN, -OH, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted -O-cycloalkyl and optionally substituted heterocyclic ring, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R ² and R ³ substituents are combined to form an optionally substituted heterocyclic ring; each R ^R3 is independently selected from hydrogen, an optionally substituted alkyl, _an optionally substituted _C3-4 carbocycle, and an optionally substituted _{3-4 membered heterocycloalkyl; R4 is selected from hydrogen, a halogen, -CN, an optionally substituted C1-4} ^alkyl _{, an} optionally substituted _C3-4 carbocycle, and _an optionally substituted _3-4 membered heterocycloalkyl; each of ^R5 and ^R6 is independently selected from hydrogen, a halogen _{, -CN} , _an optionally substituted _C1-4 alkyl, _an optionally substituted _C3-4 carbocycle, and an optionally substituted _3-4 membered heterocycloalkyl; and ^R7 is selected _from hydrogen and an optionally substituted _C1- wherein if A is an optionally substituted phenyl, m is 1 to 5 and at least one R ¹ is a heterocycloalkyl, wherein if A is ^{an optionally substituted pyridine, an optionally substituted pyrimidine or an optionally substituted pyrimidine, R 4} _is selected from hydrogen, a halogen and -CN, wherein if A is an optionally substituted piperidinesulfonamide, (i) Y ¹ is -C(R ² ) ₂ - and the two R ² substituents are combined to form a ring selected from an optionally substituted heterocycle and an optionally substituted carbocycle, or (ii) R ⁴ is selected from hydrogen, a halogen, a methyl and -CN, and wherein if AR ¹ is and Z ⁰ is CH, then R ⁴ is methyl or cyclopropyl. The compound of claim 1 or its pharmaceutically acceptable salt or solvent complex has the structure of formula (I): , wherein A is a ring selected from the following: an optionally substituted carbon ring, an optionally substituted 4- to 6-membered heterocyclic ring, and an optionally substituted isoindoline. The compound of claim 1 or 2 or a pharmaceutically acceptable salt or solvent thereof, which has a structure of one or more of formula (IA), (IB), (IC), (ID) or (IE): wherein R ⁸ is selected from halogen, -CN and an optionally substituted C _{1 - 4} alkyl; R ⁹ is selected from an optionally substituted C _{3 - 6} carbocycle, an optionally substituted C _{5 - 6} heteroaryl and a 3- to 6-membered heterocycloalkyl; R ¹⁰ is an optionally substituted alkyl or an optionally substituted heterocycloalkyl; R ¹¹ is selected from halogen, -CN and an optionally substituted C _{1 - 4} alkyl; R ¹² is selected from an optionally substituted heterocycloalkyl, an optionally substituted heterocycloalkylalkyl, an optionally substituted cycloalkyl and an optionally substituted cycloalkylalkyl; or R ¹² and R ¹³ are combined to form an optionally substituted heterocycle; R ^{R 13} is selected from halogen, -CN and _an optionally substituted C _{1-4 alkyl} group; n is selected from 0 to 9; R ¹⁴ is selected from -SOR ¹⁶ - and an optionally substituted heterocycloalkyl group; R ¹⁵ is selected from hydrogen, halogen, -CN _{and an optionally substituted C 1-4 alkyl group; R 16 is selected from an optionally substituted C 1-4 alkyl group, an optionally substituted C 3-6 carbocyclic group and an} ^optionally _{substituted 3-6 membered heterocycloalkyl} group; R ¹⁷ is selected from -SOR ¹⁹ -, an optionally substituted alkyl group, an optionally substituted carbocyclic group and an optionally substituted heterocycloalkyl group; R ¹⁸ is selected _from halogen, -CN and _an optionally substituted C _1-4 alkyl group; R ¹⁹ is selected from _{optionally substituted C 1-4 alkyl , optionally substituted C 3-6 carbocycle and} optionally substituted 3-6 membered heterocycloalkyl; r is selected from 0 to 5; p is selected from 0 to 4; q is selected from 0 to 2; and wherein when the compound has formula (IA), (i) Y ¹ is -C(R ² ) ₂ - and the two R ² substituents are combined to form a ring selected from: optionally substituted heterocycle and optionally substituted carbocycle, or (ii) R ⁴ is selected from hydrogen, halogen and -CN. The compound of claim 3 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IA). The compound of claim 3 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IB). The compound of claim 3 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IC). The compound of claim 3 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IE). The compound or pharmaceutically acceptable salt of any one of claims 1 to 7, wherein ^Z1 and ^Z2 are independently selected from -C( ^R2 ) _2- , ^-NR3- , -O- and -S-. The compound or pharmaceutically acceptable salt of claim 8, wherein Z ¹ and Z ² are independently -C(R ² ) ₂ -. The compound or pharmaceutically acceptable salt of claim 9, wherein each of a and b is independently selected from 1 and 2. The compound or pharmaceutically acceptable salt of any one of claims 1 to 10, wherein Y ¹ is selected from -C(R ² ) ₂ -, -NR ³ -, -NS(O ₂ )R ² , -O-, -S(O) ₂ - and -S-. The compound or pharmaceutically acceptable salt of claim 11, wherein Y ¹ is selected from -C(R ² ) ₂ - and -NR ³ . The compound or pharmaceutically acceptable salt of any one of claims 1 to 12, wherein each R ² is independently selected from hydrogen, OH, halogen, -CN, optionally substituted alkyl, optionally substituted -O-alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. The compound or pharmaceutically acceptable salt of claim 13, wherein each R ² is independently selected from hydrogen, halogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl. The compound of claim 14 or a pharmaceutically acceptable salt or solvent thereof, wherein each R ² is independently selected from hydrogen, -CN and cyclopropyl. The compound or pharmaceutically acceptable salt of any one of claims 1 to 15, wherein two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. The compound or pharmaceutically acceptable salt of any one of claims 1 to 15, wherein each R ³ is selected from hydrogen, optionally substituted alkyl, cyclopropyl, cyclobutyl, optionally substituted oxacyclobutane and optionally substituted azacyclobutane. The compound or pharmaceutically acceptable salt of claim 17, wherein each R ³ is selected from methyl, methoxyethylene, CD ₃ , cyclopropyl and cyclobutyl. The compound or pharmaceutically acceptable salt of claim 18, wherein R ³ is cyclopropyl. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt or solvent thereof, which has a structure of one or more of formula (IAA), (IBB), (ICC), (IDD) or (IEE): wherein R ⁸ is selected from halogen, -CN and an optionally substituted C _{1 - 4} alkyl; R ⁹ is selected from an optionally substituted C _{3 - 6} carbocyclic ring, an optionally substituted C _{5 - 6} heteroaryl group and a 3- to 6-membered heterocycloalkyl group; R ¹⁰ is an optionally substituted heterocycloalkyl group; R ¹¹ is selected from halogen, -CN and an optionally substituted C _{1 - 4} alkyl group; R ¹² is an optionally substituted heterocycloalkyl group; or R ¹² and R ¹³ are combined to form an optionally substituted heterocyclic ring; R ¹³ is selected from halogen, -CN and an optionally substituted C _{1 - 4} alkyl group; R ¹⁵ is selected from hydrogen, halogen, -CN and an optionally substituted C R ¹⁶ is selected from an optionally substituted C _{1 - 4} alkyl group, an optionally substituted C _{3 - 6} carbocycle and an optionally substituted 3 _to 6 membered heterocycloalkyl group; R ¹⁹ is selected from _{an optionally substituted C 1 - 4 alkyl} group, an optionally substituted C _{3 - 6} carbocycle and an optionally substituted 3 to ₆ membered heterocycloalkyl group; n is selected from 0 to 9; p is selected from 0 to 4; q is selected from 0 to 2; each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -C(O)-, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O-, -S-, -S(O)- and -S(O) ₂ -, wherein Z ⁵ is additionally selected from a bond; and each of a, b, c and d is independently selected from 1, 2, 3 and 4. The compound of claim 20 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IAA). The compound of claim 20 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IBB). The compound of claim 20 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (ICC). The compound of claim 20 or a pharmaceutically acceptable salt or solvent thereof, which has the structure of formula (IEE). The compound or pharmaceutically acceptable salt of any one of claims 20 to 24, wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -N(C(O)R ² )-, -NS(O ₂ )R ³ , -O- and -S(O) ₂ -, wherein Z ⁵ is further selected from a bond. The compound or pharmaceutically acceptable salt of claim 25, wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is independently selected from -C(R ² ) ₂ -, -NR ³ -, -O- and -S(O) ₂ -, and wherein Z ⁵ is further selected from a bond. The compound or pharmaceutically acceptable salt of claim 20 to 26, wherein each R ² is independently selected from hydrogen, halogen, -CN, OH, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R ² substituents are combined to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. The compound or pharmaceutically acceptable salt of claim 27, wherein each R ² is selected from hydrogen, fluorine, CN, cyclopropyl, cyclobutyl, -C _{1 - 4} alkyl, -C _{1 - 4} halogenalkyl, -OC _{1 - 4} alkyl, -C _{1 - 4} alkylene-OC _{1 - 3} alkyl, -C _{1 - 4} alkylene-OH, optionally substituted oxacyclobutane and optionally substituted azocyclobutane. The compound or pharmaceutically acceptable salt of any one of claims 20 to 28, wherein R ³ is selected from hydrogen, -(CH ₂ ) ₂ OMe, -S(O) ₂ CH ₃ , -C _{1 - 4} alkylene-OC _{1 - 3} alkyl, C _{1 - 4} alkyl, cyclopropyl, cyclobutyl, optionally substituted oxacyclobutane and optionally substituted azacyclobutane. The compound or pharmaceutically acceptable salt of claim 29, wherein R ³ is selected _from hydrogen, -(CH ₂ ) ₂ OMe, C _1-4 alkyl, _cyclopropyl , cyclobutyl, optionally substituted oxacyclobutane and optionally substituted azocyclobutane. The compound or pharmaceutically acceptable salt of claim 30, wherein R ³ is selected from hydrogen, methyl, ethyl, propyl, CD ₃ and cyclopropyl. The compound or pharmaceutically acceptable salt of any one of claims 20 to 31, wherein each of a, b, c and d is independently selected from 1 and 2. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein A is selected from optionally substituted cyclohexane, optionally substituted pyridine, optionally substituted piperidine, optionally substituted tetrahydropyran, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted azacyclobutane and optionally substituted tetrahydroisoquinoline. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted piperidine. The compound or pharmaceutically acceptable salt of claim 34, wherein A is substituted by SO ₂ R ⁹ , wherein R ⁹ is selected from an optionally substituted C _{3 - 6} carbocyclic ring, an optionally substituted C _{5 - 6} heteroaryl group and a 3- to 6-membered heterocycloalkyl group. The compound or pharmaceutically acceptable salt of claim 34 or 35, wherein m is selected from 0 to 1. The compound or pharmaceutically acceptable salt of any one of claims 34 to 36, wherein each R ¹ is independently selected from optionally substituted alkyl, optionally substituted carbocyclic and optionally substituted heterocyclic. The compound or pharmaceutically acceptable salt of claim 37, wherein each R ¹ is independently selected from an optionally substituted alkyl group and an optionally substituted heterocyclic group. The compound or pharmaceutically acceptable salt of claim 37, wherein each R ¹ is independently selected from methyl, ethyl and optionally substituted diazaspiro[3.3]heptane. The compound or pharmaceutically acceptable salt of any one of claims 1 to 13 and 34 to 39, wherein ^Z1 and ^Z2 are independently selected from -C( ^R2 ) _2- , ^-NR3- , -O- and -S-. The compound or pharmaceutically acceptable salt of claim 40, wherein ^Z1 and ^Z2 are each -C( ^R2 ) _2- . The compound or pharmaceutically acceptable salt of claim 40 or 41, wherein each of a and b is independently selected from 1 and 2. The compound or pharmaceutically acceptable salt of any one of claims 1 to 13 and 34 to 42, wherein Y ¹ is selected from -C(R ² ) ₂ -, -NR ³ -, -O- and -S-. The compound or pharmaceutically acceptable salt of claim 43, wherein Y ¹ is selected from -C(R ² ) ₂ - and -NR ³ . The compound or pharmaceutically acceptable salt of claim 44, wherein Y ¹ is -C(R ² ) ₂ -, and two R ² substituents are combined to form a ring selected from the group consisting of an optionally substituted heterocyclic ring and an optionally substituted carbocyclic ring. The compound or pharmaceutically acceptable salt of claim 45, wherein Y ¹ is -C(R ² ) ₂ -, and the two R ² substituents are combined to form a ring selected from the group consisting of an optionally substituted heterocyclic ring. A compound or a pharmaceutically acceptable salt of any one of claims 1 to 19 and 34 to 46, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is selected from an optionally substituted azacyclobutane, an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted piperidine, an optionally substituted morpholine, an optionally substituted tetrahydrothienopyrrole dioxide and an optionally substituted dihydroindole. A compound or a pharmaceutically acceptable salt of any one of claims 1 to 19 and 34 to 46, wherein the compound is represented by formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring system is selected from . The compound or pharmaceutically acceptable salt of any one of claims 1 to 32 or 34 to 48, wherein R ⁴ is selected from hydrogen, halogen, optionally substituted _{C 1-2} alkyl, optionally substituted _{C 3-4 carbocycle} and optionally substituted _3-4 membered heterocycloalkyl. The compound or pharmaceutically acceptable salt of claim 49, wherein R ⁴ is selected from hydrogen and optionally substituted C ₁ alkyl. The compound or pharmaceutically acceptable salt of claim 50, wherein R ⁴ is selected from hydrogen, methyl and -CHF ₂ . The compound or pharmaceutically acceptable salt of any one of claims 1 to 32 or 34 to 48, wherein R ⁴ is selected from hydrogen, halogen and -CN. The compound or pharmaceutically acceptable salt of any one of claims 1 to 32 or 34 to 48, wherein R ⁴ is selected from hydrogen. The compound or pharmaceutically acceptable salt of any one of claims 1 to 32 or 34 to 48, wherein R ⁴ is not optionally substituted phenyl. The compound or pharmaceutically acceptable salt of any one of claims 1 to 32 or 34 to 48, wherein R ⁴ is not optionally substituted alkyl. The compound or pharmaceutically acceptable salt of any one of claims 1 to ₃₂ , 34 to 39 or 50 to 55, wherein R ⁵ is selected _from hydrogen, halogen, optionally substituted _{C 1-2} alkyl, optionally substituted C _{3-4 carbocycle} and optionally substituted 3-4 membered heterocycloalkyl. The compound or pharmaceutically acceptable salt of claim ₅₆ , wherein R ⁵ is selected from hydrogen, halogen and optionally substituted _{C 1-2} alkyl. The compound or pharmaceutically acceptable salt of claim 57, wherein R ⁵ is selected from hydrogen and fluorine. The compound or pharmaceutically acceptable salt of any one of claims 1 to 32 _, 34 to 39 or 50 to 58, wherein ^R6 is selected _from hydrogen _, halogen, optionally substituted _C1-2 alkyl, optionally substituted _{C3-4 carbocycle} and optionally substituted 3-4 membered heterocycloalkyl. The compound or pharmaceutically acceptable salt of claim ₅₉ , wherein R ⁶ is selected from hydrogen, halogen and optionally substituted _{C 1-2} alkyl. The compound or pharmaceutically acceptable salt of claim 60, wherein R ⁶ is hydrogen. The compound or pharmaceutically acceptable salt of any one of claims 1 to 32, 34 to 39 or 50 to 61, wherein R ⁷ is hydrogen. The compound or pharmaceutically acceptable salt of any one of claims 3 to 4, 8 to 21 or 25 to 32, wherein R ⁹ is selected from cyclopentyl, methylcyclopentyl, cyclobutylmethylene, cyclopentylmethylene and n-methylpyrazolyl. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 1. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 1. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 1. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 1. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one of claims 1 to 67 and a pharmaceutically acceptable excipient. A method for treating cancer, comprising administering to a subject in need thereof a compound of any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 68. The method of claim 66, wherein the cancer is a solid tumor. The method of claim 69 or 70, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer and brain cancer. The method of claim 71, wherein the cancer is ovarian cancer or breast cancer. A method for inhibiting cyclin dependent kinase (CDK) in cells using the compound of any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 68. The method of claim 73, wherein the CDK is selected from CDK 2, CDK 4, CDK6, or any combination thereof. The method of claim 74, wherein the CDK is selected from CDK 2/4, CDK 2/6, CDK 4/6 and CDK 2/4/6. The method of claim 75, wherein the CDK is CDK 2/4/6.